PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jexpmedHomeThis articleEditorsContactInstructions for Authors
 
J Exp Med. 2016 January 11; 213(1): 1–13.
PMCID: PMC4710203
Review

Ubiquitin in the activation and attenuation of innate antiviral immunity

Abstract

Viral infection activates danger signals that are transmitted via the retinoic acid–inducible gene 1–like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and Toll-like receptor (TLR) protein signaling cascades. This places host cells in an antiviral posture by up-regulating antiviral cytokines including type-I interferon (IFN-I). Ubiquitin modifications and cross-talk between proteins within these signaling cascades potentiate IFN-I expression, and inversely, a growing number of viruses are found to weaponize the ubiquitin modification system to suppress IFN-I. Here we review how host- and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression.

The frontline in the cellular response to viral infection is comprised of the specific and general effectors of the innate immune system. Effector molecule production is initiated by immune sentinels known as pattern recognition receptors (PRRs), which screen the intra- and extracellular environment for molecular motifs uniquely associated with pathogens. PRR engagement transduces pro-immune signals into the nucleus via protein signaling cascades that self-limit to mitigate autoimmunity as the infection clears (Crampton et al., 2012). Protein posttranslational modifications (PTMs) form part of this exquisite system of regulation, with ubiquitin and ubiquitin-like modifications key among them.

The retinoic acid–inducible gene 1 (RIG-I)–like receptors (RLRs) and nucleotide-binding oligomerization domain (NOD)–like receptors (NLRs) are intracellular PRRs. The RLRs sense invasive RNA produced during infection by both RNA and DNA viruses (Schlee, 2013). RLR engagement up-regulates type-I IFN (IFN-I) expression, which in turn stimulates transcription of hundreds of IFN-stimulated genes (ISGs) that commit host and nearby cells to an antiviral posture. Recognized for their role in antibacterial immunity, the NLRs are emerging as antiviral mediators that regulate both IFN-I and NF-κB activation. These are also activated by TLRs, a cell-specific class of extracellular and endosomal transmembrane PRRs that sense a broad spectrum of pathogenic motifs. RLR, NLR, and TLR signaling proteins must be spatially and temporally coordinated for efficient immune signal transduction.

Ubiquitination is a PTM involving the covalent attachment of the 8.6-kD protein ubiquitin to target proteins. Ubiquitination is catalyzed by the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin protein ligase (E3). The E3 largely dictates substrate specificity, with at least 617 genes encoding putative ubiquitin and ubiquitin-like E3s annotated in the human genome (Li et al., 2008). Ubiquitin can undergo ubiquitination itself at its seven lysine residues (K6/K11/K27/K29/K33/K48/K63), building lysine-linked polyubiquitin chains, or its N-terminal methionine (M1), forming linear polyubiquitin chains. Alternatively, ubiquitin chains may be noncovalently associated with target proteins. Furthermore, ubiquitin chains may be remodeled by deubiquitinating enzymes (DUbs; Fig. 1). The function, abundance, or subcellular distribution of proteins involved in almost every cellular process is regulated in this way, with an increasingly clear role in regulating innate immunity.

Figure 1.
The ubiquitin modification system and mechanisms of viral manipulation. (1) Ubiquitin (Ub) expresses as an inactive polyprotein, encoded by the UBB and UBC genes. DUbs cleave this polyprotein into monomers that are activated by the E1-activating enzyme, ...

Viruses are obligate intracellular parasites that facilitate their own replication by manipulating the host cell environment. Thus, the ubiquitin modification system presents a key manipulation target for viruses to circumvent antiviral signaling pathways. Methods for this include substrate molecular mimicry, binding and blocking E3-substrate pairs, expressing virally encoded E3s/DUbs, and hijacking host E3s/DUbs. Additionally, a novel mechanism involving ubiquitin chain packaging into nascent virions for subsequent redeployment against the host was recently described (Banerjee et al., 2014). Although characterizing the molecular mechanisms of ubiquitin-dependent immune signaling remains challenging, this information is essential in understanding innate immune regulation and mechanisms of viral immune evasion.

RLR signaling

Pattern recognition and cascade initiation

RIG-I and melanoma differentiation-associated gene 5 receptor (MDA5), together with the regulatory homologue laboratory of genetics and physiology 2 (LGP2), form the apex of the RLR signaling cascade. All three are expressed ubiquitously, but only RIG-I and MDA5 possess N-terminal caspase activation and recruitment domains (CARDs) that are capable of downstream immune signal transduction.

Based on their distinctive C-terminal domains that sense different types of invasive RNA, the RLRs are activated by different viruses. RNA lacking a 5′-7-methylguanosine cap, a feature of mature eukaryotic RNA, potently activates MDA5-mediated signaling (Züst et al., 2011). Except during viral infection, the mammalian cytosol is normally vacant of immature 5′-triphosphorylated RNA, certain kinds of which activate RIG-I (Schlee et al., 2009).

RLR activation up-regulates expression of two IFN-I isotypes, IFN-α and IFN-β, which regulate transcription of hundreds of ISGs during infection (Fig. 2, middle). IFN regulatory factors (IRFs), including IRF3 and IRF7, dimerize and translocate into the nucleus to drive transcription of various IFN-α/β subtypes upon phosphorylation by TNF receptor–associated factor (TRAF) family member–associated NF-κB activator (TANK)–binding kinase 1 (TBK1). TBK1 localization changes from the cytosol to distinct subcellular compartments depending on upstream signaling events (Goncalves et al., 2011). In promoting IFN-I signaling, TBK1 associates with RIG-I as well as key adaptor proteins, including TANK and NF-κB essential modulator (NEMO; Guo and Cheng, 2007; Zhao et al., 2007; Wang et al., 2012a). This facilitates interactions between TBK1, inhibitor of NF-κB kinase subunit ε (IKKε) and TRAFs, particularly TRAF3. Upon RLR activation, these proteins are colocalized at the cytosolic surface of the mitochondrial outer membrane (Parvatiyar et al., 2010; van Zuylen et al., 2012), coordinated by the mitochondrial antiviral-signaling protein (MAVS; also termed VISA/Cardif/IPS-1).

Figure 2.
Schematic of the TLR, RLR, and NLR antiviral protein signaling cascades and modes of cross-talk. PRRs (blue) screen the intracellular and extracellular environment for pathogenic motifs. Ligand-activated PRRs bind adaptor proteins (purple) and recruit ...

At rest, the RLR cascade is maintained in an inactive but tensioned state through an intricate negative feedback system involving protein expression levels, conformational changes, compartmentalization, and PTMs. Part of this system operates at the receptor through conformational auto-inhibition of the RIG-I CARDs. The RIG-I C-terminal repressor domain (RD) audits the cytosol for viral RNA, binding of which induces a major structural rearrangement in the RD and CARD (Saito et al., 2007). Conversely, MDA5 oligomerizes along the length of RNA ligands, forming immunogenic filaments that are potentiated by ATP hydrolysis and interaction with LGP2 (Peisley et al., 2012; Bruns et al., 2014).

RIG-I activation depends on ubiquitin

The unfurled RIG-I CARDs undergo tetramerization upon K63-linked polyubiquitination or unanchored polyubiquitin chain association (Peisley et al., 2014). These modifications drive mitochondrial accumulation of RIG-I, promoting CARD–CARD interactions with MAVS and inducing its oligomerization and filamentation. The RIG-I CARDs contain a high proportion of hydrophobic residues and are prone to aggregation, thus oligomerization and polyubiquitination may stabilize the activated CARDs or elicit a separate mitochondrial targeting signal. Conversely, ubiquitination has no known role in MDA5 or LGP2 activation.

The first virus-triggered RIG-I ubiquitination site described, K172, depends on the E3 activity of tripartite motif protein 25 (TRIM25; Gack et al., 2007). Plausibly as a means of restricting escape mutant selection, this activation mechanism now appears to have evolved with partial redundancy using alternate E3s. TRIM4 was recently described to modify this same site in addition to two other CARD residues: K154 and K164 (Yan et al., 2014). Furthermore, these same three residues are reportedly ubiquitinated by really interesting new gene (RING) finger protein-135 (RNF135; also termed Riplet/REUL; Gao et al., 2009), although this is controversial (Fig. 3; Oshiumi et al., 2010). Underscoring the importance of these modifications, ubiquitin-specific protease 3 (USP3) and ubiquitin C-terminal hydrolase are DUbs that inhibit IFN-I production by removing such chains from RIG-I (Friedman et al., 2008; Cui et al., 2014).

Figure 3.
Effect on IFN-I expression of ubiquitin modifications to key RLR cascade proteins and mechanisms of manipulation by human-tropic viruses. Ubiquitin modification site and ubiquitin chain linkage type are shown in blue circles. Ubiquitin modifications that ...

Both TRIM25 and RNF135 are targets of the influenza A virus (IAV) nonstructural protein 1 (NS1), which blocks their E3 activity and ubiquitin-dependent RIG-I activation (Fig. 3; Gack et al., 2009; Rajsbaum et al., 2012). IAV-NS1 binds the central coiled-coil domain (CCD) of TRIM25 and is postulated to prevent CCD-mediated homo-oligomerization. Although the NS1-binding site on RNF135 is unknown, RNF135 and TRIM25 share a similar RING-CCD-B30.2/SPRY (sp1A and ryanodine receptors) domain organization. However, the CCDs differ in size and sequence markedly, suggesting that IAV-NS1 may bind multiple sites on TRIM25 and RNF135. Alternatively, given that CCDs often mediate protein–protein interactions, IAV-NS1 may sense and subvert CCD-interacting domains more broadly. Notably, the IAV-NS1:RNF135 interactions observed by Rajsbaum et al. (2012) were strain dependent.

RNF135 enables RIG-I CARD activation by TRIM25 upon ubiquitinating RD residues K849 and K851. RNF135 knockdown inhibits interaction between RIG-I:TRIM25 and eliminates TBK1 recruitment (Oshiumi et al., 2009), revealing an ordered functional interplay between ubiquitination and phosphorylation in coordinating RIG-I activation. Hepatitis C virus (HCV) NS3-4A protease exploits this concept by targeting RNF135 for proteolytic cleavage (Oshiumi et al., 2013). Furthermore, numerous herpesviruses encode their own DUbs that inhibit IFN-I expression by stripping ubiquitin modifications from activated RIG-I (Inn et al., 2011b). Accordingly, HCV and herpesvirus infections are treatable with IFN (Oberman and Panet, 1988; Nguyen et al., 2014), although this can carry significant side effects. Endogenous IFN-I expression and self-regulation may be restored by defeating such mechanisms of viral antagonism.

Ubiquitin in the return to homeostasis

RLR signaling is also counterbalanced and diminished through ubiquitin modification as the antiviral posture becomes unnecessary. RNF125 forms part of this process, ligating K48-linked polyubiquitin chains to the activated CARD of RIG-I and MDA5, leading to proteasome-mediated degradation of both receptors and diminished IFN-I signaling. USP4 is a DUb that sustains RLR signaling by specifically removing such chains (Wang et al., 2013a). In the same way, RNF125 ubiquitinates and degrades activated MAVS (Arimoto et al., 2007), suggesting that RNF125 is an E3 that destabilizes proteins containing activated CARDs. Given how commonly CARD-containing proteins and their homotypic interactions feature in immune signaling pathways (Bouchier-Hayes and Martin, 2002), RNF125 may represent a general immune signaling antagonist. Conversely, the 52-kD repressor of the inhibitor of the protein kinase (p52rIPK) binds and enhances the stability of RIG-I by blocking its ubiquitin-mediated degradation (Now and Yoo, 2011). Accordingly, the properties of p52rIPK or RNF125 may be exploitable in the treatment of viral infections or autoimmune disorders.

The linear ubiquitin assembly complex (LUBAC), containing SHANK-associated RH domain–interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1L (HOIL-1L), and HOIL-1–interacting protein (HOIP), was proposed to negatively regulate RLR-mediated IFN-I expression via two independent mechanisms (Inn et al., 2011a). First, HOIL-1L competes with TRIM25 for RIG-I CARD binding, abrogating the RIG-I:MAVS interaction. Second, HOIP promotes M1- and K48-linked polyubiquitination of TRIM25 and induces its proteasomal degradation, thereby decreasing TRIM25-mediated activation of RIG-I. If LUBAC were capable of ligating K48-linked polyubiquitin chains to substrates, TRIM25 would be the first example to our knowledge.

Another route of RLR inhibition involves tetraspanin-6 ubiquitination by an unknown E3. During RLR activation, polyubiquitinated tetraspanin-6 is recruited to MAVS and blocks the RLR:MAVS interaction, thereby impeding recruitment of the downstream signaling apparatus (Wang et al., 2012b).

Convergence at MAVS

Mitochondria, peroxisomes, and endoplasmic reticulum function as immune signaling platforms linking viral pattern recognition with effector molecule production (Fig. 2, middle). Although this process remains poorly characterized, the nature and context of viral ligands detected by PRRs drives accumulation of the downstream signaling apparatus to these platforms. Adaptor proteins mediate this accumulation: mitochondria and peroxisomes by MAVS (Dixit et al., 2010) and endoplasmic reticulum by stimulator of IFN genes (STING; Ishikawa and Barber, 2008). Cyclic GMP-AMP synthase (cGAS) and AIM2-like receptors (ALRs), which include AIM2 and human IFN-inducible protein 16 (IFI16), have also emerged as important DNA virus PRRs. cGAS signals via STING and AIM2 generates inflammasome oligomers, whereas IFI16 can stimulate both signaling mechanisms (Diner et al., 2015).

RNA-activated RIG-I and MDA5 colocalize with MAVS, inducing its filamentation. It remains unclear why these filaments are potent inducers of downstream signaling; however, RLR cascade proteins including NEMO, IKKε, and various TRAFs possess MAVS-targeting signals (Paz et al., 2011). Furthermore, TBK1 and other key RLR cascade proteins interact with these proteins but are activated only upon oligomerization. Thus, steady state isolation of MAVS may represent a spatiotemporal barrier that restrains innate immune signaling, overcome through coordinating these proteins into signaling complexes upon MAVS multimerization. In this way, it is conceivable how immunomodulating E3s/DUbs may be compartmentalized together with their substrates.

Ubiquitin stringently regulates the MAVS signalosome

The central position that MAVS occupies within the RLR cascade is commensurate with the many PTMs that modulate its role. To our knowledge, MAVS ubiquitination has not been observed in resting cells using a variety of proteomic and biochemical approaches, indicating that MAVS ubiquitination occurs specifically during viral infection. At least seven E3s ubiquitinate MAVS, leading to MAVS degradation in almost every case, as described later in this section (Fig. 3). At least five of these modify other substrates within the same cascade, highlighting MAVS as a crucial locus of RLR regulation. Accordingly, MAVS is targeted by numerous viruses in a variety of ways; however, with the exception of HBV and severe acute respiratory syndrome–coronavirus (SARS-CoV; Fig. 3; Wei et al., 2010; Shi et al., 2014), this is usually achieved by means other than manipulating MAVS ubiquitination, likely given the extensive ubiquitin-mediated negative regulatory systems already in place.

MAVS aggregation is a key feature of RLR cascade activation, but how these aggregates are resolved during deactivation is only beginning to be clarified. In addition to ubiquitinating RIG-I and enhancing its association with MAVS, TRIM25 ubiquitinates MAVS at Lys7 and Lys10 and induces its partial proteolysis (Castanier et al., 2012). This was proposed as a means of discharging the activated RLR signalosome from the mitochondrial recruitment platform and would begin to address how IRF3 and other RLR signalosome components traffic correctly after activation. More recently, Lys7 and Lys500 were shown to be polyubiquitinated by membrane-associated RING finger protein 5 (MARCH5), a mitochondrial membrane-bound E3 that effectively dissolves MAVS aggregates by specifically targeting them for degradation. MARCH5 is an important regulator of mitochondrial fission and fusion whose expression is up-regulated during infection (Yoo et al., 2015). These mechanisms of MAVS aggregate resolution may be nonredundant, with the TRIM25 mechanism occurring throughout the immune response and the MARCH5 mechanism amplifying gradually in an IFN-I negative feedback loop.

Complete MAVS degradation is independently promoted by the E3s RNF5, RNF125, atrophin-1–interacting protein 4 (AIP4; also termed ITCH), SMAD ubiquitination regulatory factor 1 (Smurf1), and Smurf2 (Fig. 3). RNF5 polyubiquitinates MAVS at Lys362 and Lys461, whereas the adjacent residues Lys371 and Lys420 are polyubiquitinated by AIP4 upon recruitment by poly(rC)-binding protein 1 (PCBP1) or PCBP2 (You et al., 2009; Zhong et al., 2010; Zhou et al., 2012). AIP4 additionally inhibits IFN-I as well as NF-κB activation by ubiquitinating the inhibitor of apoptosis protein 1 (cIAP1), targeting it for lysosomal degradation (Tigno-Aranjuez et al., 2013). cIAP1 is an E3 that activates TRAF3/6 during viral infection (Mao et al., 2010), revealing that AIP4 broadly and multiply inhibits NLR-, RLR-, and TLR-mediated immune signaling. The acceptor site or sites for RNF125-induced MAVS ubiquitination are unknown; however, given that RNF125 also ubiquitinates the activated CARDs of RIG-I and MDA5 (Arimoto et al., 2007), the MAVS CARD appears a likely candidate. NEDD4 family–interacting protein 1 (Ndfip1) binds MAVS and recruits Smurf1 and possibly Smurf2, facilitating ubiquitination of unknown sites within MAVS (Wang et al., 2012c; Pan et al., 2014). Moreover, numerous TRAFs, including TRAF3 and TRAF6, interact with MAVS, and Smurf1 also targets these for degradation (Li et al., 2010a). Finally, Lys500 was reported as a single site of IFN-I–activating polyubiquitination by an unknown E3, inhibiting NF-κB activation by sequestering IKKε (Paz et al., 2009).

TRAF ubiquitination orients immune signal transmission

The TRAFs are six multifunctional adaptor proteins that regulate both NF-κB activation and IFN-I expression via the RLR, NLR, and TLR protein signaling cascades (Fig. 2). TRAF-mediated signaling outcomes are augmented by ubiquitin, and, excepting TRAF1, all TRAFs possess a RING finger domain and multiple zinc coordination sites, features typical of ubiquitin E3s. K63-linked autoubiquitination at Lys124 is a key activation mechanism of TRAF6 (Lamothe et al., 2007; Jiao et al., 2015) and possibly TRAF2 (Habelhah et al., 2004), TRAF4 (Marinis et al., 2012), and TRAF5 (Zhong et al., 2012). In vitro TRAF3 ubiquitination assays and analysis of recombinant TRAF3ΔRING isolated from mammalian cell lysates are also consistent with an autoubiquitination activation mechanism for TRAF3 (Kayagaki et al., 2007; Zeng et al., 2009).

TRAF3 and TRAF6 are among the first molecules activated by MAVS in the RLR pathway (Fig. 2, middle). Furthermore, there is increasing evidence of ubiquitin-mediated cross-talk between TRAFs. TRAF3 promotes IFN-I expression by activating TBK1/IRF3 (Parvatiyar et al., 2010), whereas TRAF6 activates mitogen-activated protein kinase kinase kinase 1 (MEKK1) to activate NF-κB, which also enhances IFN-I expression (Yoshida et al., 2008). Simultaneously, TRAF3 suppresses NF-κB by inhibiting IKK activation upon binding TRAF2 (Zarnegar et al., 2008), likely as a mechanism to skew innate immune effector molecule expression as required. Inversely, the E3 cIAP2, after itself being ubiquitinated by TRAF6, promotes TRAF3 degradation by ligating K48-linked polyubiquitin chains to TRAF3 at residues K107 and K156, thereby restoring NF-κB activation (Tseng et al., 2010). However, as well as degrading TRAF3, cIAP1/2 can also activate TRAF3 by catalyzing its K63-linked polyubiquitination (Fig. 3; Mao et al., 2010). This suggests that the context-dependent ubiquitination state of cIAP1/2 determines its effect on TRAF3. The E3 RNF166 was recently reported to ubiquitinate and activate both TRAF3 and TRAF6 (Chen et al., 2015). Finally, the RIG-I–activating E3 TRIM25 was reported to enhance MDA5-mediated NF-κB activation at the level of TRAF6 (Lee et al., 2015), although mechanistic details remain unclear.

TRAF-mediated signaling is also terminated by ubiquitin in numerous ways. HSV encodes the DUb UL36USP, which strips K63-linked polyubiquitin chains from TRAF3 to prevent downstream protein recruitment (Fig. 3; Wang et al., 2013b), possibly antagonizing cIAP1/2-mediated ubiquitination. TRAF3 and TRAF6 are both deactivated by the DUbs otubain 1 (OTUB1) and OTUB2, which remove K63-linked polyubiquitin chains (Li et al., 2010b). TRAF3 is further deactivated by the deubiquitinase DUBA, which removes K63-linked polyubiquitin chains from TRAF3 (Kayagaki et al., 2007). Furthermore, the E3 Triad3A redirects TRAF3 to the proteasome by ligating K48-linked polyubiquitin chains (Nakhaei et al., 2009). Altogether, this constitutes a ubiquitin-dependent feedback mechanism that enables TRAFs to dictate the direction of immune signal transmission in a context-dependent manner.

The NLRs: An emerging force in antiviral immunity

In contrast to the three RLR receptors, the 22 NLRs have diverse expression patterns and largely under-characterized functions. The NLRs are well recognized for their roles in regulating NF-κB activation and antibacterial immunity; however, at least five members have emerging roles in antiviral immune signaling: NOD1, NOD2, NLRC5 (NLR family CARD domain–containing protein 5), NLRP4 (NACHT, LRR, and PYD domain–containing protein 4), and NLRX1 (NLR family member X1; Fig. 2, right). Although NLRs recruit E3s and modulate the ubiquitination of other proteins, including several in the RLR cascade, the role of PTMs in NLR regulation remains under-defined.

NLR regulation and innate immune signaling cross-talk

The PRRs NOD1 and NOD2 are the best characterized NLRs. NOD1 is expressed ubiquitously, whereas NOD2 is expressed mainly in cells of myeloid and lymphoid origin and is up-regulated during bacterial and viral infection. The classic NOD2-activating ligand is bacterial muramyl dipeptide (MDP), which promotes NF-κB activation. However, NOD2 also promotes IFN-I expression during infection by numerous RNA viruses, in part through recognizing single-stranded RNA (ssRNA) and interacting with MAVS. NOD2 may also promote IFN-I expression during infection by particular DNA viruses by an undefined mechanism (Sabbah et al., 2009; Kapoor et al., 2014). Accordingly, NOD2 dysfunction leads to inefficient innate and adaptive immune responses to viral infection (Lupfer et al., 2014).

NOD2 features regularly in the immune signaling landscape, yet mechanisms of NOD2 regulation and cross-talk are only beginning to be revealed. Upon activation by MDP, NOD2 is ubiquitinated by TRIM27, leading to NOD2 degradation and NF-κB inhibition (Zurek et al., 2012). NOD2 signaling is further suppressed by AIP4, which ubiquitinates Lys209 of receptor-interacting serine/threonine protein kinase 2 (RIPK2), the immediate downstream interacting partner of NOD2 (Fig. 2, right; Tao et al., 2009). Conversely, NOD2-driven NF-κB activation is enhanced by LUBAC, a negative regulator of RLR signaling, as well as X-linked IAP (XIAP), which respectively ligate M1- and K63-linked polyubiquitin chains to NOD2 and RIPK2 (Damgaard et al., 2012). These activating ubiquitin chains may be antagonized by the ubiquitin-editing enzyme A20 (Hitotsumatsu et al., 2008), which also disrupts ubiquitin-mediated TBK1 activation in the RLR signaling cascade as well as ubiquitin-mediated TRAF6 activation in the TLR cascade (Turer et al., 2008; Parvatiyar et al., 2010).

Another mitochondrial link between the NLR and RLR signaling pathways is the ubiquitously expressed NLRX1 (Fig. 2, right), whose role in IFN-I regulation is controversial. NLRX1 is localized to the mitochondrial outer membrane and was reported to inhibit MAVS-dependent IFN-I signaling by blocking the interaction between activated RIG-I/MDA5 and MAVS, although viral replication experiments using gene knockout cells have produced conflicting results (Soares et al., 2013). NLRX1 also potentiates NF-κB signaling by promoting reactive oxygen species production during bacterial infection, linking the mitochondrial immune signaling platform with proinflammatory cytokine generation (Tattoli et al., 2008).

NLRC5 was initially described to enhance IFN-γ and IFN-α expression and inhibit NF-κB and IFN-β, in the latter case through sequestering the activated effector domains of RIG-I and MDA5 (Cui et al., 2010; Kuenzel et al., 2010). NLRC5 has also been shown to bind and inhibit TBK1-mediated IFN-β induction in HEK-293T cells, although NLRC5−/− mice show relatively normal cytokine responses upon exposure to RLR-, TLR-, and NLR-activating stimuli (Kumar et al., 2011). Still other findings indicate that the RIG-I:NLRC5 interaction also positively regulates IFN-β expression, and this interaction is targeted by the IAV-NS1 protein (Fig. 2, right; Neerincx et al., 2010; Ranjan et al., 2015). These disparate conclusions may reflect cell-specific differences given that NLRC5 is predominantly expressed in hematopoietic cells or differences between mouse and human signaling pathways, suggesting that the NLRC5 regulatory framework is complex. Adding to this, ubiquitination plays an uncharacterized role in regulating NLRC5 upon LPS stimulation and may be induced by NLRC5 overexpression (Cui et al., 2010; Kuenzel et al., 2010). Given the diversity of interactions that NLRC5 takes part in, it is likely that further PTMs will be shown to regulate NLRC5 during viral infection.

NLRP4 has gained prominence as another negative regulator of multiple immune signaling pathways that is more widely expressed than NLRC5. NLRP4 was initially described to inhibit IKKα-mediated NF-κB activation (Fiorentino et al., 2002). Upon RLR cascade activation, NLRP4 also inhibits IRF3 activation by recruiting the E3 deltex-4 (DTX4) to ubiquitinate and degrade TBK1 (Cui et al., 2012), revealing yet another route for RLR/NLR cross-talk (Fig. 2, right).

TLR signaling

TLRs are differentially expressed in a wide range of cell populations. TLR3, TLR7, TLR8, and TLR9 are expressed in endosomal vesicles, whereas TLR2 and TLR4 are expressed on the cell surface. TLR3 recognizes double-stranded RNA, activating NF-κB–mediated proinflammatory cytokine production and strongly up-regulating TBK1/IRF3-dependent IFN-I expression. TLR7 and TLR8 recognize ssRNA, up-regulating IFN-α and proinflammatory cytokine production. TLR9 recognizes unmethylated cytosine-phosphate-guanine (CpG) DNA, a common feature of nonmammalian genomes, and stimulates IFN-α production. TLR2 and TLR4 are activated by a variety of microbial ligands, including specific viral proteins, resulting in proinflammatory cytokine expression (Fig. 2, left).

NF-κB activation and IFN-I up-regulation

TLR2, TLR4, TLR7, TLR8, and TLR9 signaling is mediated through the adaptor protein myeloid differentiation primary response gene 88 (MyD88; Fig. 2, left). MyD88 recruits NF-κB and IFN-I signaling components, including interleukin-1 receptor–associated kinase 1 (IRAK1), IRAK4, TRAF6, and IRF7. Activated TRAF6 ubiquitinates IRF7, leading to IFN-α expression (Kawai et al., 2004). TRAF6 also promotes K63-linked polyubiquitination of NEMO, enabling recruitment of the TGF-β–activated kinase (TAB)–TAK1 kinase complex (Tseng et al., 2010). Subsequent association between NEMO and M1-polyubiquitin chains induces TAK1-mediated phosphorylation of IKKα and IKKβ, priming them for full transactivation through autophosphorylation (Zhang et al., 2014). Activated IKKα phosphorylates the IκBα subunit, leading to its ubiquitination and proteasomal degradation and releasing NF-κB for nuclear translocation. Furthermore, MyD88, IRAK1/4, and TAB2/3 are also modified and activated by K63-linked polyubiquitin chains. Such chains were recently described as substrates for M1-polyubiquitination by HOIP, resulting in hybrid chains that may connect the MyD88/IRAK and TAK1/IKK signaling apparatus (Emmerich et al., 2013). TLR3 signaling is mediated by TIR domain–containing adaptor-inducing IFN-β (TRIF). TRIF activates TRAF3, which promotes IRF3/IRF7 activation (Tseng et al., 2010), and also TRAF6, which promotes IKK activation (Fig. 2, left; Jiang et al., 2004).

Ubiquitin regulates the MyD88- and TRIF-dependent pathways

Although TLRs undergo extensive PTM, ubiquitination performs no known role in regulating TLRs directly. Instead, ubiquitination modulates their downstream signaling targets, particularly MyD88, TRIF, and TRAF6, and it is often here that viruses terminate TLR-mediated immunity.

Nrdp1 is an E3 that promotes IFN-I expression at the expense of proinflammatory cytokines. TBK1 polyubiquitination by Nrdp1 activates TBK1 in TRIF-mediated IFN-I expression, which simultaneously K48-polyubiquitinates and down-regulates MyD88-mediated NF-κB activation (Wang et al., 2009). Conversely, the ubiquitin-editing enzyme A20 inhibits ubiquitin-mediated activation of TRAF6, inhibiting NF-κB activation via the TLR and NLR cascades, as well as TBK1, inhibiting IFN-I expression (Hitotsumatsu et al., 2008; Turer et al., 2008; Parvatiyar et al., 2010). Additional avenues of signaling cross-talk include Smurf1 and Smurf2, which degrade MAVS and inhibit IFN-I activation. Smurf1 and Smurf2 also degrade MyD88, inhibiting TLR-mediated NF-κB activation (Lee et al., 2011).

cIAP2 is an E3 that, after itself being ubiquitinated by TRAF6, targets TRAF3 for degradation (Tseng et al., 2010). This is important in promoting TLR4-mediated signaling and cytokine production at the expense of type I IFN production (Zhong et al., 2013). Furthermore, TRAF6 itself promotes proinflammatory cytokine production at the expense of IFN-I. TRAF6 is activated by trans-autoubiquitination at K124, abolition of which eliminates NEMO ubiquitination and TAK1 activation (Lamothe et al., 2007). This mechanism is exploited by HSV, which uses the virally encoded E3 infected cell polypeptide 0 (ICP0) to recruit USP7 to deubiquitinate NEMO and TRAF6 (Daubeuf et al., 2009). In addition, ICP0 directly catalyzes ubiquitination and degradation of MyD88 and TIRAP (Toll/interleukin-1 receptor domain–containing adaptor protein; van Lint et al., 2010). Kaposi’s sarcoma–associated herpesvirus (KSHV) encodes replication and transcription factor (RTA), an E3 that activates latent virus. This activation process involves suppression of antiviral cytokines, partly involving RTA-catalyzed ubiquitination and degradation of MyD88 and TRIF (Ahmad et al., 2011; Zhao et al., 2015), thereby impairing all TLR-mediated immune signaling pathways.

The final relay: IRFs transmit danger signals into the nucleus

TLR, NLR, and RLR IFN-I signaling converges at IRF activation, the penultimate step toward IFN-I transcription. IRF3 is constitutively expressed in most cell types, residing inactive in the cytosol until phosphorylation by TBK1/IKKε within two activation clusters (Ser385/Ser386 and Ser396/Ser398/Ser402/Thr404/Ser405), resulting in homodimerization, nuclear accumulation, DNA binding, and participation in IFNB gene transcription (Lin et al., 1998). IFN-β acts in an autocrine and paracrine manner upon its cognate receptor, IFN-α/β receptor (IFNAR), thereby activating JAK/STAT signaling and ISG expression. IRF7 expression is up-regulated in this way, which in turn activates IFNA transcription and additional ISG expression by a similar mechanism.

Ubiquitin is an IRF master toggle

The IRFs are among the most tightly controlled IFN-I signaling proteins through an interplay of PTMs, including phosphorylation, ubiquitination, and ubiquitin-like modifications. Phosphorylation of IRF7 at Ser477 and Ser479 by TBK1/IKKε is required for its activation (tenOever et al., 2004). However, ubiquitination by TRAF6 at nearby residues Lys444, Lys446, and Lys452 appears to be a prerequisite to this and serves as a link between the NF-κB and IFN-I activation pathways (Ning et al., 2008). Furthermore, TRIM28 binds active IRF7 and ligates small ubiquitin-like modifier (SUMO) at two of these ubiquitination sites, Lys444 and Lys446, negatively regulating virus-triggered IFN-α production (Liang et al., 2011), indicating that as yet unidentified DUbs or deSUMOylating enzymes participate in regulating IRF7.

Reminiscent of IRF7, IRF3 residues Lys70 and Lys87 accept both polyubiquitin chains and SUMO, and competition between these modifications can determine the fate of IFN-I signal transduction. At steady state, the SUMO-conjugating enzyme ubiquitin carrier protein 9 (Ubc9) protects IRF3 from ubiquitin-mediated degradation by occupying these sites with SUMO. Alternatively, the deSUMOylating enzyme sentrin-specific protease 2 (SENP2) removes SUMO from IRF3, enabling its K48-linked polyubiquitination (Ran et al., 2011). Subsequent work identified TRIM26 as an E3 that conjugates K48-linked polyubiquitin chains to these same sites (Fig. 3; Wang et al., 2015), triggering degradation of the active, nuclear-localized form of IRF3. Furthermore, activated IRF3 undergoes phosphorylation at Ser339. This promotes interaction with peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1), a nuclear-localized protein that promotes IRF3 degradation (Saitoh et al., 2006). The E3 recruited by Pin1 for this purpose is unknown; however, TRIM26 is also localized to the nucleus and seems a strong candidate.

IRF3 degradation is undesirable at early stages of the innate immune response and is limited in several ways. The IRF3-Pin1 interaction is inhibited by the HECT (homologous to the E6-AP C terminus) domain and RCC1-like domain–containing protein 5 (HERC5), which ligates another ubiquitin-like protein, ISG15, onto IRF3 at Lys193, Lys360, and Lys366, thereby sustaining IRF3 activation (Shi et al., 2010). TRIM21 is a ubiquitin E3 described to both inhibit the IRF3-Pin1 interaction and target IRF3 for proteasomal degradation (Higgs et al., 2008; Yang et al., 2009). TRIM21 reportedly also targets IRF7 for degradation upon TLR7 or TLR9 activation (Higgs et al., 2010), although the TRIM21-dependent IRF3/IFR7 ubiquitin acceptor sites remain undefined (Fig. 3).

Several additional E3s regulate IRF abundance. The Skp-Cullin–F-box (SCF)–containing complex, of which cullin1 (Cul1) is a core component, catalyzes IRF3 degradation as well as IκB degradation, promoting NF-κB activation (Fig. 3; Bibeau-Poirier et al., 2006). RanBP-type and C3HC4-type zinc finger–containing protein 1 (RBCK1) catalyzes K48-linked polyubiquitination and degradation of IRF3 during viral infection (Fig. 3; Zhang et al., 2008). Finally, the forkhead box protein O1 (FoxO1), a regulator of insulin signaling, binds IRF3 and promotes its degradation by recruiting an unknown E3. FoxO1 also negatively regulates IRF7 transcription (Lei et al., 2013), altogether implying a link between metabolism and innate immune induction. Expression of Cul1 and the E3s RBCK1, TRIM21, TRIM26, and HERC5 is IFN-I inducible (Henig et al., 2013), constituting a multiply redundant negative feedback web in which IFN-I expression is self-restraining.

Not so fast: Seizing the penultimate step toward antiviral gene transcription

IRFs are a significant target of viral disruption, usually resulting in their proteasome-mediated degradation. Rotavirus (RoV) nonstructural protein 1 blocks NF-κB signaling and usurps the ubiquitin modification system to redirect IRF3/5/7/9 to the proteasome in a strain-specific manner (Fig. 3; Morelli et al., 2015). Cells produce trace quantities of IFN-I at rest through basal activation of endogenous IRF3/IRF7, the intracellular concentration of which are regulated by the E3 RTA-associated ubiquitin ligase (RAUL). KSHV exploits this mechanism to diminish immune signaling, recruiting USP7 to deubiquitinate RAUL and thereby maintain RAUL-mediated IRF3/IRF7 degradation (Yu and Hayward, 2010). The RAUL-dependent ubiquitin acceptor sites on IRF3/IRF7 remain unknown (Fig. 3), but better characterization of the RAUL-IRF interaction may have implications for antiviral and autoimmunity treatments. Furthermore, the KSHV RTA protein catalyzes polyubiquitination and degradation of IRF7 and MyD88 (Yu et al., 2005). Thus, KSHV effectively terminates several signaling pathways at multiple stages.

Similar to KSHV, HIV infection fails to stimulate activation of IRF3, endogenous levels of which are quickly reduced upon infection. Underscoring the importance for HIV to disrupt early IFN-I–mediated immunity, IRF3 degradation is independently promoted by two viral accessory proteins, viral infectivity factor (Vif) and viral protein R (Vpr). The E3s hijacked for this purpose are unknown (Fig. 3), although Vif and Vpr recruit SCF-related components to degrade other antiviral proteins (Okumura et al., 2008).

Concluding remarks

The innate immune signaling architecture is complex and has coevolved with the pathogens it guards against, meanwhile restraining autoimmunity through an elaborate negative feedback scheme. A cornerstone of this dynamic regulatory framework is the ubiquitin modification system, which is manipulated by viruses relevant to human disease. Going forward in understanding mechanisms of infection and autoimmunity, we must address significant gaps in knowledge regarding the specificity and context-dependent regulation of E3s and DUbs and the consequences of ubiquitin modification. This will expose further cross-talk between the immune signaling cascades, revealing a functional and self-regulating whole. In the search for a new generation of antiviral and autoimmune treatments, we continue to learn from the pathogens that have long adapted to exploit this ready-made system of functional regulation; humans possess hundreds of specific- and general-effect E3s and DUbs, many of which could be harnessed for therapeutic use.

ACKNOWLEDGMENTS

We are grateful to Dr. Sarah Atkinson for critical review of the manuscript.

N.A. Borg is an Australian Research Council (ARC) Future Fellow (FT110100223).

The authors declare no competing financial interests.

Footnotes

Abbreviations used:

CARD
caspase activation and recruitment domain
CCD
coiled-coil domain
DUb
deubiquitinating enzyme
HOIP
HOIL-1–interacting protein
IAV
influenza A virus
IKK
inhibitor of NF-κB kinase
IRF
IFN regulatory factor
ISG
IFN-stimulated gene
KSHV
Kaposi’s sarcoma–associated herpesvirus
LUBAC
linear ubiquitin assembly complex
MAVS
mitochondrial antiviral signaling protein
NEMO
NF-κB essential modulator
NLR
NOD-like receptor
PRR
pattern recognition receptor
PTM
posttranslational modification
RAUL
RTA-associated ubiquitin ligase
RD
repressor domain
RING
really interesting new gene
RLR
RIG-I–like receptor
RTA
replication and transcription factor
SUMO
small ubiquitin-like modifier
TRAF
TNF receptor–associated factor
TRIF
TIR domain–containing adaptor-inducing IFN-β

References

  • Ahmad H., Gubbels R., Ehlers E., Meyer F., Waterbury T., Lin R., and Zhang L. 2011. Kaposi sarcoma-associated herpesvirus degrades cellular Toll-interleukin-1 receptor domain-containing adaptor-inducing β-interferon (TRIF). J. Biol. Chem. 286:7865–7872. 10.1074/jbc.M110.191452 [PMC free article] [PubMed] [Cross Ref]
  • Arimoto K., Takahashi H., Hishiki T., Konishi H., Fujita T., and Shimotohno K. 2007. Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc. Natl. Acad. Sci. USA. 104:7500–7505. 10.1073/pnas.0611551104 [PubMed] [Cross Ref]
  • Banerjee I., Miyake Y., Nobs S.P., Schneider C., Horvath P., Kopf M., Matthias P., Helenius A., and Yamauchi Y. 2014. Influenza A virus uses the aggresome processing machinery for host cell entry. Science. 346:473–477. 10.1126/science.1257037 [PubMed] [Cross Ref]
  • Bibeau-Poirier A., Gravel S.P., Clément J.F., Rolland S., Rodier G., Coulombe P., Hiscott J., Grandvaux N., Meloche S., and Servant M.J. 2006. Involvement of the IκB kinase (IKK)-related kinases tank-binding kinase 1/IKKi and cullin-based ubiquitin ligases in IFN regulatory factor-3 degradation. J. Immunol. 177:5059–5067. 10.4049/jimmunol.177.8.5059 [PubMed] [Cross Ref]
  • Bouchier-Hayes L., and Martin S.J. 2002. CARD games in apoptosis and immunity. EMBO Rep. 3:616–621. 10.1093/embo-reports/kvf139 [PubMed] [Cross Ref]
  • Bruns A.M., Leser G.P., Lamb R.A., and Horvath C.M. 2014. The innate immune sensor LGP2 activates antiviral signaling by regulating MDA5-RNA interaction and filament assembly. Mol. Cell. 55:771–781. 10.1016/j.molcel.2014.07.003 [PMC free article] [PubMed] [Cross Ref]
  • Castanier C., Zemirli N., Portier A., Garcin D., Bidère N., Vazquez A., and Arnoult D. 2012. MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors. BMC Biol. 10:44 10.1186/1741-7007-10-44 [PMC free article] [PubMed] [Cross Ref]
  • Chen H.W., Yang Y.K., Xu H., Yang W.W., Zhai Z.H., and Chen D.Y. 2015. Ring finger protein 166 potentiates RNA virus-induced interferon-β production via enhancing the ubiquitination of TRAF3 and TRAF6. Sci. Rep. 5:14770 10.1038/srep14770 [PMC free article] [PubMed] [Cross Ref]
  • Crampton S.P., Deane J.A., Feigenbaum L., and Bolland S. 2012. Ifih1 gene dose effect reveals MDA5-mediated chronic type I IFN gene signature, viral resistance, and accelerated autoimmunity. J. Immunol. 188:1451–1459. 10.4049/jimmunol.1102705 [PMC free article] [PubMed] [Cross Ref]
  • Cui J., Zhu L., Xia X., Wang H.Y., Legras X., Hong J., Ji J., Shen P., Zheng S., Chen Z.J., and Wang R.F. 2010. NLRC5 negatively regulates the NF-κB and type I interferon signaling pathways. Cell. 141:483–496. 10.1016/j.cell.2010.03.040 [PMC free article] [PubMed] [Cross Ref]
  • Cui J., Li Y., Zhu L., Liu D., Songyang Z., Wang H.Y., and Wang R.F. 2012. NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4. Nat. Immunol. 13:387–395. 10.1038/ni.2239 [PMC free article] [PubMed] [Cross Ref]
  • Cui J., Song Y., Li Y., Zhu Q., Tan P., Qin Y., Wang H.Y., and Wang R.F. 2014. USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors. Cell Res. 24:400–416. 10.1038/cr.2013.170 [PMC free article] [PubMed] [Cross Ref]
  • Damgaard R.B., Nachbur U., Yabal M., Wong W.W., Fiil B.K., Kastirr M., Rieser E., Rickard J.A., Bankovacki A., Peschel C., et al. 2012. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol. Cell. 46:746–758. 10.1016/j.molcel.2012.04.014 [PubMed] [Cross Ref]
  • Daubeuf S., Singh D., Tan Y., Liu H., Federoff H.J., Bowers W.J., and Tolba K. 2009. HSV ICP0 recruits USP7 to modulate TLR-mediated innate response. Blood. 113:3264–3275. 10.1182/blood-2008-07-168203 [PubMed] [Cross Ref]
  • Diner B.A., Lum K.K., and Cristea I.M. 2015. The emerging role of nuclear viral DNA sensors. J. Biol. Chem. 290:26412–26421. 10.1074/jbc.R115.652289 [PMC free article] [PubMed] [Cross Ref]
  • Dixit E., Boulant S., Zhang Y., Lee A.S., Odendall C., Shum B., Hacohen N., Chen Z.J., Whelan S.P., Fransen M., et al. 2010. Peroxisomes are signaling platforms for antiviral innate immunity. Cell. 141:668–681. 10.1016/j.cell.2010.04.018 [PMC free article] [PubMed] [Cross Ref]
  • Emmerich C.H., Ordureau A., Strickson S., Arthur J.S., Pedrioli P.G., Komander D., and Cohen P. 2013. Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains. Proc. Natl. Acad. Sci. USA. 110:15247–15252. 10.1073/pnas.1314715110 [PubMed] [Cross Ref]
  • Fiorentino L., Stehlik C., Oliveira V., Ariza M.E., Godzik A., and Reed J.C. 2002. A novel PAAD-containing protein that modulates NF-κB induction by cytokines tumor necrosis factor-α and interleukin-1β. J. Biol. Chem. 277:35333–35340. 10.1074/jbc.M200446200 [PubMed] [Cross Ref]
  • Friedman C.S., O’Donnell M.A., Legarda-Addison D., Ng A., Cárdenas W.B., Yount J.S., Moran T.M., Basler C.F., Komuro A., Horvath C.M., et al. 2008. The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep. 9:930–936. 10.1038/embor.2008.136 [PubMed] [Cross Ref]
  • Gack M.U., Shin Y.C., Joo C.H., Urano T., Liang C., Sun L., Takeuchi O., Akira S., Chen Z., Inoue S., and Jung J.U. 2007. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature. 446:916–920. 10.1038/nature05732 [PubMed] [Cross Ref]
  • Gack M.U., Albrecht R.A., Urano T., Inn K.S., Huang I.C., Carnero E., Farzan M., Inoue S., Jung J.U., and García-Sastre A. 2009. Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe. 5:439–449. 10.1016/j.chom.2009.04.006 [PMC free article] [PubMed] [Cross Ref]
  • Gao D., Yang Y.K., Wang R.P., Zhou X., Diao F.C., Li M.D., Zhai Z.H., Jiang Z.F., and Chen D.Y. 2009. REUL is a novel E3 ubiquitin ligase and stimulator of retinoic-acid-inducible gene-I. PLoS One. 4:e5760 10.1371/journal.pone.0005760 [PMC free article] [PubMed] [Cross Ref]
  • Goncalves A., Bürckstümmer T., Dixit E., Scheicher R., Górna M.W., Karayel E., Sugar C., Stukalov A., Berg T., Kralovics R., et al. 2011. Functional dissection of the TBK1 molecular network. PLoS One. 6:e23971 10.1371/journal.pone.0023971 [PMC free article] [PubMed] [Cross Ref]
  • Guo B., and Cheng G. 2007. Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK. J. Biol. Chem. 282:11817–11826. 10.1074/jbc.M700017200 [PubMed] [Cross Ref]
  • Habelhah H., Takahashi S., Cho S.G., Kadoya T., Watanabe T., and Ronai Z. 2004. Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF-κB. EMBO J. 23:322–332. 10.1038/sj.emboj.7600044 [PubMed] [Cross Ref]
  • Henig N., Avidan N., Mandel I., Staun-Ram E., Ginzburg E., Paperna T., Pinter R.Y., and Miller A. 2013. Interferon-beta induces distinct gene expression response patterns in human monocytes versus T cells. PLoS One. 8:e62366 10.1371/journal.pone.0062366 [PMC free article] [PubMed] [Cross Ref]
  • Higgs R., Ní Gabhann J., Ben Larbi N., Breen E.P., Fitzgerald K.A., and Jefferies C.A. 2008. The E3 ubiquitin ligase Ro52 negatively regulates IFN-β production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. J. Immunol. 181:1780–1786. 10.4049/jimmunol.181.3.1780 [PMC free article] [PubMed] [Cross Ref]
  • Higgs R., Lazzari E., Wynne C., Ní Gabhann J., Espinosa A., Wahren-Herlenius M., and Jefferies C.A. 2010. Self protection from anti-viral responses—Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors. PLoS One. 5:e11776 10.1371/journal.pone.0011776 [PMC free article] [PubMed] [Cross Ref]
  • Hitotsumatsu O., Ahmad R.C., Tavares R., Wang M., Philpott D., Turer E.E., Lee B.L., Shiffin N., Advincula R., Malynn B.A., et al. 2008. The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity. 28:381–390. 10.1016/j.immuni.2008.02.002 [PMC free article] [PubMed] [Cross Ref]
  • Inn K.S., Gack M.U., Tokunaga F., Shi M., Wong L.Y., Iwai K., and Jung J.U. 2011. a Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type I interferon induction. Mol. Cell. 41:354–365. 10.1016/j.molcel.2010.12.029 [PMC free article] [PubMed] [Cross Ref]
  • Inn K.S., Lee S.H., Rathbun J.Y., Wong L.Y., Toth Z., Machida K., Ou J.H., and Jung J.U. 2011. b Inhibition of RIG-I-mediated signaling by Kaposi’s sarcoma-associated herpesvirus-encoded deubiquitinase ORF64. J. Virol. 85:10899–10904. 10.1128/JVI.00690-11 [PMC free article] [PubMed] [Cross Ref]
  • Ishikawa H., and Barber G.N. 2008. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 455:674–678. 10.1038/nature07317 [PMC free article] [PubMed] [Cross Ref]
  • Jiang Z., Mak T.W., Sen G., and Li X. 2004. Toll-like receptor 3-mediated activation of NF-κB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-β. Proc. Natl. Acad. Sci. USA. 101:3533–3538. 10.1073/pnas.0308496101 [PubMed] [Cross Ref]
  • Jiao S., Zhang Z., Li C., Huang M., Shi Z., Wang Y., Song X., Liu H., Li C., Chen M., et al. 2015. The kinase MST4 limits inflammatory responses through direct phosphorylation of the adaptor TRAF6. Nat. Immunol. 16:246–257. 10.1038/ni.3097 [PubMed] [Cross Ref]
  • Kapoor A., Forman M., and Arav-Boger R. 2014. Activation of nucleotide oligomerization domain 2 (NOD2) by human cytomegalovirus initiates innate immune responses and restricts virus replication. PLoS One. 9:e92704 10.1371/journal.pone.0092704 [PMC free article] [PubMed] [Cross Ref]
  • Kawai T., Sato S., Ishii K.J., Coban C., Hemmi H., Yamamoto M., Terai K., Matsuda M., Inoue J., Uematsu S., et al. 2004. Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 5:1061–1068. 10.1038/ni1118 [PubMed] [Cross Ref]
  • Kayagaki N., Phung Q., Chan S., Chaudhari R., Quan C., O’Rourke K.M., Eby M., Pietras E., Cheng G., Bazan J.F., et al. 2007. DUBA: a deubiquitinase that regulates type I interferon production. Science. 318:1628–1632. 10.1126/science.1145918 [PubMed] [Cross Ref]
  • Kuenzel S., Till A., Winkler M., Häsler R., Lipinski S., Jung S., Grötzinger J., Fickenscher H., Schreiber S., and Rosenstiel P. 2010. The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses. J. Immunol. 184:1990–2000. 10.4049/jimmunol.0900557 [PubMed] [Cross Ref]
  • Kumar H., Pandey S., Zou J., Kumagai Y., Takahashi K., Akira S., and Kawai T. 2011. NLRC5 deficiency does not influence cytokine induction by virus and bacteria infections. J. Immunol. 186:994–1000. 10.4049/jimmunol.1002094 [PubMed] [Cross Ref]
  • Lamothe B., Besse A., Campos A.D., Webster W.K., Wu H., and Darnay B.G. 2007. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of IκB kinase activation. J. Biol. Chem. 282:4102–4112. 10.1074/jbc.M609503200 [PMC free article] [PubMed] [Cross Ref]
  • Lee N.R., Kim H.I., Choi M.S., Yi C.M., and Inn K.S. 2015. Regulation of MDA5-MAVS antiviral signaling axis by TRIM25 through TRAF6-mediated NF-κB activation. Mol. Cells. 38:759–764. 10.14348/molcells.2015.0047 [PMC free article] [PubMed] [Cross Ref]
  • Lee Y.S., Park J.S., Kim J.H., Jung S.M., Lee J.Y., Kim S.J., and Park S.H. 2011. Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling. Nat. Commun. 2:460 10.1038/ncomms1469 [PubMed] [Cross Ref]
  • Lei C.Q., Zhang Y., Xia T., Jiang L.Q., Zhong B., and Shu H.B. 2013. FoxO1 negatively regulates cellular antiviral response by promoting degradation of IRF3. J. Biol. Chem. 288:12596–12604. 10.1074/jbc.M112.444794 [PMC free article] [PubMed] [Cross Ref]
  • Li S., Lu K., Wang J., An L., Yang G., Chen H., Cui Y., Yin X., Xie P., Xing G., et al. 2010. a Ubiquitin ligase Smurf1 targets TRAF family proteins for ubiquitination and degradation. Mol. Cell. Biochem. 338:11–17. 10.1007/s11010-009-0315-y [PubMed] [Cross Ref]
  • Li S., Zheng H., Mao A.P., Zhong B., Li Y., Liu Y., Gao Y., Ran Y., Tien P., and Shu H.B. 2010. b Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6. J. Biol. Chem. 285:4291–4297. 10.1074/jbc.M109.074971 [PMC free article] [PubMed] [Cross Ref]
  • Li W., Bengtson M.H., Ulbrich A., Matsuda A., Reddy V.A., Orth A., Chanda S.K., Batalov S., and Joazeiro C.A.P. 2008. Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling. PLoS One. 3:e1487 10.1371/journal.pone.0001487 [PMC free article] [PubMed] [Cross Ref]
  • Liang Q., Deng H., Li X., Wu X., Tang Q., Chang T.H., Peng H., Rauscher F.J. III, Ozato K., and Zhu F. 2011. Tripartite motif-containing protein 28 is a small ubiquitin-related modifier E3 ligase and negative regulator of IFN regulatory factor 7. J. Immunol. 187:4754–4763. 10.4049/jimmunol.1101704 [PMC free article] [PubMed] [Cross Ref]
  • Lin R., Heylbroeck C., Pitha P.M., and Hiscott J. 1998. Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Mol. Cell. Biol. 18:2986–2996. 10.1128/MCB.18.5.2986 [PMC free article] [PubMed] [Cross Ref]
  • Lupfer C., Thomas P.G., and Kanneganti T.D. 2014. Nucleotide oligomerization and binding domain 2-dependent dendritic cell activation is necessary for innate immunity and optimal CD8+ T Cell responses to influenza A virus infection. J. Virol. 88:8946–8955. 10.1128/JVI.01110-14 [PMC free article] [PubMed] [Cross Ref]
  • Mao A.P., Li S., Zhong B., Li Y., Yan J., Li Q., Teng C., and Shu H.B. 2010. Virus-triggered ubiquitination of TRAF3/6 by cIAP1/2 is essential for induction of interferon-β (IFN-β) and cellular antiviral response. J. Biol. Chem. 285:9470–9476. 10.1074/jbc.M109.071043 [PMC free article] [PubMed] [Cross Ref]
  • Marinis J.M., Hutti J.E., Homer C.R., Cobb B.A., Cantley L.C., McDonald C., and Abbott D.W. 2012. IκB kinase α phosphorylation of TRAF4 downregulates innate immune signaling. Mol. Cell. Biol. 32:2479–2489. 10.1128/MCB.00106-12 [PMC free article] [PubMed] [Cross Ref]
  • Morelli M., Dennis A.F., and Patton J.T. 2015. Putative E3 ubiquitin ligase of human rotavirus inhibits NF-κB activation by using molecular mimicry to target β-TrCP. MBio. 6:e02490-14 10.1128/mBio.02490-14 [PMC free article] [PubMed] [Cross Ref]
  • Nakhaei P., Mesplede T., Solis M., Sun Q., Zhao T., Yang L., Chuang T.H., Ware C.F., Lin R., and Hiscott J. 2009. The E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation. PLoS Pathog. 5:e1000650 10.1371/journal.ppat.1000650 [PMC free article] [PubMed] [Cross Ref]
  • Neerincx A., Lautz K., Menning M., Kremmer E., Zigrino P., Hösel M., Büning H., Schwarzenbacher R., and Kufer T.A. 2010. A role for the human nucleotide-binding domain, leucine-rich repeat-containing family member NLRC5 in antiviral responses. J. Biol. Chem. 285:26223–26232. 10.1074/jbc.M110.109736 [PMC free article] [PubMed] [Cross Ref]
  • Nguyen N.H., McCormack S.A., Yee B.E., Devaki P., Jencks D., Chao D.T., and Nguyen M.H. 2014. Meta-analysis of patients with hepatitis C virus genotype 6: 48 weeks with pegylated interferon and ribavirin is superior to 24 weeks. Hepatol. Int. 8:540–549. 10.1007/s12072-014-9570-4 [PubMed] [Cross Ref]
  • Ning S., Campos A.D., Darnay B.G., Bentz G.L., and Pagano J.S. 2008. TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1. Mol. Cell. Biol. 28:6536–6546. 10.1128/MCB.00785-08 [PMC free article] [PubMed] [Cross Ref]
  • Now H., and Yoo J.Y. 2011. A protein-kinase, IFN-inducible double-stranded RNA dependent inhibitor and repressor of p58 (PRKRIR) enhances type I IFN-mediated antiviral response through the stability control of RIG-I protein. Biochem. Biophys. Res. Commun. 413:487–493. 10.1016/j.bbrc.2011.08.127 [PubMed] [Cross Ref]
  • Oberman F., and Panet A. 1988. Inhibition of transcription of herpes simplex virus immediate early genes in interferon-treated human cells. J. Gen. Virol. 69:1167–1177. 10.1099/0022-1317-69-6-1167 [PubMed] [Cross Ref]
  • Okumura A., Alce T., Lubyova B., Ezelle H., Strebel K., and Pitha P.M. 2008. HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation. Virology. 373:85–97. 10.1016/j.virol.2007.10.042 [PMC free article] [PubMed] [Cross Ref]
  • Oshiumi H., Matsumoto M., Hatakeyama S., and Seya T. 2009. Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-β induction during the early phase of viral infection. J. Biol. Chem. 284:807–817. 10.1074/jbc.M804259200 [PubMed] [Cross Ref]
  • Oshiumi H., Miyashita M., Inoue N., Okabe M., Matsumoto M., and Seya T. 2010. The ubiquitin ligase Riplet is essential for RIG-I-dependent innate immune responses to RNA virus infection. Cell Host Microbe. 8:496–509. 10.1016/j.chom.2010.11.008 [PubMed] [Cross Ref]
  • Oshiumi H., Miyashita M., Matsumoto M., and Seya T. 2013. A distinct role of Riplet-mediated K63-Linked polyubiquitination of the RIG-I repressor domain in human antiviral innate immune responses. PLoS Pathog. 9:e1003533 10.1371/journal.ppat.1003533 [PMC free article] [PubMed] [Cross Ref]
  • Pan Y., Li R., Meng J.L., Mao H.T., Zhang Y., and Zhang J. 2014. Smurf2 negatively modulates RIG-I-dependent antiviral response by targeting VISA/MAVS for ubiquitination and degradation. J. Immunol. 192:4758–4764. 10.4049/jimmunol.1302632 [PubMed] [Cross Ref]
  • Parvatiyar K., Barber G.N., and Harhaj E.W. 2010. TAX1BP1 and A20 inhibit antiviral signaling by targeting TBK1-IKKi kinases. J. Biol. Chem. 285:14999–15009. 10.1074/jbc.M110.109819 [PMC free article] [PubMed] [Cross Ref]
  • Paz S., Vilasco M., Arguello M., Sun Q., Lacoste J., Nguyen T.L., Zhao T., Shestakova E.A., Zaari S., Bibeau-Poirier A., et al. 2009. Ubiquitin-regulated recruitment of IκB kinase ε to the MAVS interferon signaling adapter. Mol. Cell. Biol. 29:3401–3412. 10.1128/MCB.00880-08 [PMC free article] [PubMed] [Cross Ref]
  • Paz S., Vilasco M., Werden S.J., Arguello M., Joseph-Pillai D., Zhao T., Nguyen T.L., Sun Q., Meurs E.F., Lin R., and Hiscott J. 2011. A functional C-terminal TRAF3-binding site in MAVS participates in positive and negative regulation of the IFN antiviral response. Cell Res. 21:895–910. 10.1038/cr.2011.2 [PMC free article] [PubMed] [Cross Ref]
  • Peisley A., Jo M.H., Lin C., Wu B., Orme-Johnson M., Walz T., Hohng S., and Hur S. 2012. Kinetic mechanism for viral dsRNA length discrimination by MDA5 filaments. Proc. Natl. Acad. Sci. USA. 109:E3340–E3349. 10.1073/pnas.1208618109 [PubMed] [Cross Ref]
  • Peisley A., Wu B., Xu H., Chen Z.J., and Hur S. 2014. Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I. Nature. 509:110–114. 10.1038/nature13140 [PubMed] [Cross Ref]
  • Rajsbaum R., Albrecht R.A., Wang M.K., Maharaj N.P., Versteeg G.A., Nistal-Villán E., García-Sastre A., and Gack M.U. 2012. Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein. PLoS Pathog. 8:e1003059 10.1371/journal.ppat.1003059 [PMC free article] [PubMed] [Cross Ref]
  • Ran Y., Liu T.T., Zhou Q., Li S., Mao A.P., Li Y., Liu L.J., Cheng J.K., and Shu H.B. 2011. SENP2 negatively regulates cellular antiviral response by deSUMOylating IRF3 and conditioning it for ubiquitination and degradation. J. Mol. Cell Biol. 3:283–292. 10.1093/jmcb/mjr020 [PubMed] [Cross Ref]
  • Ranjan P., Singh N., Kumar A., Neerincx A., Kremmer E., Cao W., Davis W.G., Katz J.M., Gangappa S., Lin R., et al. 2015. NLRC5 interacts with RIG-I to induce a robust antiviral response against influenza virus infection. Eur. J. Immunol. 45:758–772. 10.1002/eji.201344412 [PubMed] [Cross Ref]
  • Sabbah A., Chang T.H., Harnack R., Frohlich V., Tominaga K., Dube P.H., Xiang Y., and Bose S. 2009. Activation of innate immune antiviral responses by Nod2. Nat. Immunol. 10:1073–1080. 10.1038/ni.1782 [PMC free article] [PubMed] [Cross Ref]
  • Saito T., Hirai R., Loo Y.M., Owen D., Johnson C.L., Sinha S.C., Akira S., Fujita T., and Gale M. Jr 2007. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc. Natl. Acad. Sci. USA. 104:582–587. 10.1073/pnas.0606699104 [PubMed] [Cross Ref]
  • Saitoh T., Tun-Kyi A., Ryo A., Yamamoto M., Finn G., Fujita T., Akira S., Yamamoto N., Lu K.P., and Yamaoka S. 2006. Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Nat. Immunol. 7:598–605. 10.1038/ni1347 [PubMed] [Cross Ref]
  • Schlee M. 2013. Master sensors of pathogenic RNA - RIG-I like receptors. Immunobiology. 218:1322–1335. 10.1016/j.imbio.2013.06.007 [PubMed] [Cross Ref]
  • Schlee M., Roth A., Hornung V., Hagmann C.A., Wimmenauer V., Barchet W., Coch C., Janke M., Mihailovic A., Wardle G., et al. 2009. Recognition of 5′ triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity. 31:25–34. 10.1016/j.immuni.2009.05.008 [PMC free article] [PubMed] [Cross Ref]
  • Shi C.S., Qi H.Y., Boularan C., Huang N.N., Abu-Asab M., Shelhamer J.H., and Kehrl J.H. 2014. SARS-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome. J. Immunol. 193:3080–3089. 10.4049/jimmunol.1303196 [PMC free article] [PubMed] [Cross Ref]
  • Shi H.X., Yang K., Liu X., Liu X.Y., Wei B., Shan Y.F., Zhu L.H., and Wang C. 2010. Positive regulation of interferon regulatory factor 3 activation by Herc5 via ISG15 modification. Mol. Cell. Biol. 30:2424–2436. 10.1128/MCB.01466-09 [PMC free article] [PubMed] [Cross Ref]
  • Soares F., Tattoli I., Wortzman M.E., Arnoult D., Philpott D.J., and Girardin S.E. 2013. NLRX1 does not inhibit MAVS-dependent antiviral signalling. Innate Immun. 19:438–448. 10.1177/1753425912467383 [PubMed] [Cross Ref]
  • Tao M., Scacheri P.C., Marinis J.M., Harhaj E.W., Matesic L.E., and Abbott D.W. 2009. ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways. Curr. Biol. 19:1255–1263. 10.1016/j.cub.2009.06.038 [PMC free article] [PubMed] [Cross Ref]
  • Tattoli I., Carneiro L.A., Jéhanno M., Magalhaes J.G., Shu Y., Philpott D.J., Arnoult D., and Girardin S.E. 2008. NLRX1 is a mitochondrial NOD-like receptor that amplifies NF-κB and JNK pathways by inducing reactive oxygen species production. EMBO Rep. 9:293–300. 10.1038/sj.embor.7401161 [PubMed] [Cross Ref]
  • tenOever B.R., Sharma S., Zou W., Sun Q., Grandvaux N., Julkunen I., Hemmi H., Yamamoto M., Akira S., Yeh W.C., et al. 2004. Activation of TBK1 and IKKε kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity. J. Virol. 78:10636–10649. 10.1128/JVI.78.19.10636-10649.2004 [PMC free article] [PubMed] [Cross Ref]
  • Tigno-Aranjuez J.T., Bai X., and Abbott D.W. 2013. A discrete ubiquitin-mediated network regulates the strength of NOD2 signaling. Mol. Cell. Biol. 33:146–158. 10.1128/MCB.01049-12 [PMC free article] [PubMed] [Cross Ref]
  • Tseng P.H., Matsuzawa A., Zhang W., Mino T., Vignali D.A., and Karin M. 2010. Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat. Immunol. 11:70–75. 10.1038/ni.1819 [PMC free article] [PubMed] [Cross Ref]
  • Turer E.E., Tavares R.M., Mortier E., Hitotsumatsu O., Advincula R., Lee B., Shifrin N., Malynn B.A., and Ma A. 2008. Homeostatic MyD88-dependent signals cause lethal inflammation in the absence of A20. J. Exp. Med. 205:451–464. 10.1084/jem.20071108 [PMC free article] [PubMed] [Cross Ref]
  • van Lint A.L., Murawski M.R., Goodbody R.E., Severa M., Fitzgerald K.A., Finberg R.W., Knipe D.M., and Kurt-Jones E.A. 2010. Herpes simplex virus immediate-early ICP0 protein inhibits Toll-like receptor 2-dependent inflammatory responses and NF-κB signaling. J. Virol. 84:10802–10811. 10.1128/JVI.00063-10 [PMC free article] [PubMed] [Cross Ref]
  • van Zuylen W.J., Doyon P., Clément J.F., Khan K.A., D’Ambrosio L.M., Dô F., St-Amant-Verret M., Wissanji T., Emery G., Gingras A.C., et al. 2012. Proteomic profiling of the TRAF3 interactome network reveals a new role for the ER-to-Golgi transport compartments in innate immunity. PLoS Pathog. 8:e1002747 10.1371/journal.ppat.1002747 [PMC free article] [PubMed] [Cross Ref]
  • Wang C., Chen T., Zhang J., Yang M., Li N., Xu X., and Cao X. 2009. The E3 ubiquitin ligase Nrdp1 ‘preferentially’ promotes TLR-mediated production of type I interferon. Nat. Immunol. 10:744–752. 10.1038/ni.1742 [PubMed] [Cross Ref]
  • Wang L., Li S., and Dorf M.E. 2012. a NEMO binds ubiquitinated TANK-binding kinase 1 (TBK1) to regulate innate immune responses to RNA viruses. PLoS One. 7:e43756 10.1371/journal.pone.0043756 [PMC free article] [PubMed] [Cross Ref]
  • Wang L., Zhao W., Zhang M., Wang P., Zhao K., Zhao X., Yang S., and Gao C. 2013. a USP4 positively regulates RIG-I-mediated antiviral response through deubiquitination and stabilization of RIG-I. J. Virol. 87:4507–4515. 10.1128/JVI.00031-13 [PMC free article] [PubMed] [Cross Ref]
  • Wang P., Zhao W., Zhao K., Zhang L., and Gao C. 2015. TRIM26 negatively regulates interferon-β production and antiviral response through polyubiquitination and degradation of nuclear IRF3. PLoS Pathog. 11:e1004726 10.1371/journal.ppat.1004726 [PMC free article] [PubMed] [Cross Ref]
  • Wang S., Wang K., Li J., and Zheng C. 2013. b Herpes simplex virus 1 ubiquitin-specific protease UL36 inhibits beta interferon production by deubiquitinating TRAF3. J. Virol. 87:11851–11860. 10.1128/JVI.01211-13 [PMC free article] [PubMed] [Cross Ref]
  • Wang Y., Tong X., Omoregie E.S., Liu W., Meng S., and Ye X. 2012. b Tetraspanin 6 (TSPAN6) negatively regulates retinoic acid-inducible gene I-like receptor-mediated immune signaling in a ubiquitination-dependent manner. J. Biol. Chem. 287:34626–34634. 10.1074/jbc.M112.390401 [PMC free article] [PubMed] [Cross Ref]
  • Wang Y., Tong X., and Ye X. 2012. c Ndfip1 negatively regulates RIG-I-dependent immune signaling by enhancing E3 ligase Smurf1-mediated MAVS degradation. J. Immunol. 189:5304–5313. 10.4049/jimmunol.1201445 [PubMed] [Cross Ref]
  • Wei C., Ni C., Song T., Liu Y., Yang X., Zheng Z., Jia Y., Yuan Y., Guan K., Xu Y., et al. 2010. The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein. J. Immunol. 185:1158–1168. 10.4049/jimmunol.0903874 [PubMed] [Cross Ref]
  • Yan J., Li Q., Mao A.P., Hu M.M., and Shu H.B. 2014. TRIM4 modulates type I interferon induction and cellular antiviral response by targeting RIG-I for K63-linked ubiquitination. J. Mol. Cell Biol. 6:154–163. 10.1093/jmcb/mju005 [PubMed] [Cross Ref]
  • Yang K., Shi H.X., Liu X.Y., Shan Y.F., Wei B., Chen S., and Wang C. 2009. TRIM21 is essential to sustain IFN regulatory factor 3 activation during antiviral response. J. Immunol. 182:3782–3792. 10.4049/jimmunol.0803126 [PubMed] [Cross Ref]
  • Yoo Y.S., Park Y.Y., Kim J.H., Cho H., Kim S.H., Lee H.S., Kim T.H., Sun Kim Y., Lee Y., Kim C.J., et al. 2015. The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling. Nat. Commun. 6:7910 10.1038/ncomms8910 [PMC free article] [PubMed] [Cross Ref]
  • Yoshida R., Takaesu G., Yoshida H., Okamoto F., Yoshioka T., Choi Y., Akira S., Kawai T., Yoshimura A., and Kobayashi T. 2008. TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway. J. Biol. Chem. 283:36211–36220. 10.1074/jbc.M806576200 [PMC free article] [PubMed] [Cross Ref]
  • You F., Sun H., Zhou X., Sun W., Liang S., Zhai Z., and Jiang Z. 2009. PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. Nat. Immunol. 10:1300–1308. 10.1038/ni.1815 [PubMed] [Cross Ref]
  • Yu Y., and Hayward G.S. 2010. The ubiquitin E3 ligase RAUL negatively regulates type I interferon through ubiquitination of the transcription factors IRF7 and IRF3. Immunity. 33:863–877. 10.1016/j.immuni.2010.11.027 [PMC free article] [PubMed] [Cross Ref]
  • Yu Y., Wang S.E., and Hayward G.S. 2005. The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Immunity. 22:59–70. 10.1016/j.immuni.2004.11.011 [PubMed] [Cross Ref]
  • Zarnegar B., Yamazaki S., He J.Q., and Cheng G. 2008. Control of canonical NF-κB activation through the NIK-IKK complex pathway. Proc. Natl. Acad. Sci. USA. 105:3503–3508. 10.1073/pnas.0707959105 [PubMed] [Cross Ref]
  • Zeng W., Xu M., Liu S., Sun L., and Chen Z.J. 2009. Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3. Mol. Cell. 36:315–325. 10.1016/j.molcel.2009.09.037 [PMC free article] [PubMed] [Cross Ref]
  • Zhang J., Clark K., Lawrence T., Peggie M.W., and Cohen P. 2014. An unexpected twist to the activation of IKKβ: TAK1 primes IKKβ for activation by autophosphorylation. Biochem. J. 461:531–537. 10.1042/BJ20140444 [PMC free article] [PubMed] [Cross Ref]
  • Zhang M., Tian Y., Wang R.P., Gao D., Zhang Y., Diao F.C., Chen D.Y., Zhai Z.H., and Shu H.B. 2008. Negative feedback regulation of cellular antiviral signaling by RBCK1-mediated degradation of IRF3. Cell Res. 18:1096–1104. 10.1038/cr.2008.277 [PubMed] [Cross Ref]
  • Zhao Q., Liang D., Sun R., Jia B., Xia T., Xiao H., and Lan K. 2015. Kaposi’s sarcoma-associated herpesvirus-encoded replication and transcription activator impairs innate immunity via ubiquitin-mediated degradation of myeloid differentiation factor 88. J. Virol. 89:415–427. 10.1128/JVI.02591-14 [PMC free article] [PubMed] [Cross Ref]
  • Zhao T., Yang L., Sun Q., Arguello M., Ballard D.W., Hiscott J., and Lin R. 2007. The NEMO adaptor bridges the nuclear factor-κB and interferon regulatory factor signaling pathways. Nat. Immunol. 8:592–600. 10.1038/ni1465 [PubMed] [Cross Ref]
  • Zhong B., Zhang Y., Tan B., Liu T.T., Wang Y.Y., and Shu H.B. 2010. The E3 ubiquitin ligase RNF5 targets virus-induced signaling adaptor for ubiquitination and degradation. J. Immunol. 184:6249–6255. 10.4049/jimmunol.0903748 [PubMed] [Cross Ref]
  • Zhong B., Liu X., Wang X., Chang S.H., Liu X., Wang A., Reynolds J.M., and Dong C. 2012. Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin-specific protease USP25. Nat. Immunol. 13:1110–1117. 10.1038/ni.2427 [PMC free article] [PubMed] [Cross Ref]
  • Zhong B., Liu X., Wang X., Liu X., Li H., Darnay B.G., Lin X., Sun S.C., and Dong C. 2013. Ubiquitin-specific protease 25 regulates TLR4-dependent innate immune responses through deubiquitination of the adaptor protein TRAF3. Sci. Signal. 6:ra35 10.1126/scisignal.2003708 [PubMed] [Cross Ref]
  • Zhou X., You F., Chen H., and Jiang Z. 2012. Poly(C)-binding protein 1 (PCBP1) mediates housekeeping degradation of mitochondrial antiviral signaling (MAVS). Cell Res. 22:717–727. 10.1038/cr.2011.184 [PMC free article] [PubMed] [Cross Ref]
  • Zurek B., Schoultz I., Neerincx A., Napolitano L.M., Birkner K., Bennek E., Sellge G., Lerm M., Meroni G., Söderholm J.D., and Kufer T.A. 2012. TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal degradation. PLoS One. 7:e41255 10.1371/journal.pone.0041255 [PMC free article] [PubMed] [Cross Ref]
  • Züst R., Cervantes-Barragan L., Habjan M., Maier R., Neuman B.W., Ziebuhr J., Szretter K.J., Baker S.C., Barchet W., Diamond M.S., et al. 2011. Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat. Immunol. 12:137–143. 10.1038/ni.1979 [PMC free article] [PubMed] [Cross Ref]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press