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author:("Sun, liuwei")
1.  Activation of Smurf E3 Ligase Promoted by Smoothened Regulates Hedgehog Signaling through Targeting Patched Turnover 
PLoS Biology  2013;11(11):e1001721.
Protein turnover of Patched, the Hedgehog receptor and key negative regulator of Hedgehog signaling, is controlled by the ubiquitin E3 ligase, Smurf, in a manner that depends on activation of signal transducer, Smoothened.
Hedgehog signaling plays conserved roles in controlling embryonic development; its dysregulation has been implicated in many human diseases including cancers. Hedgehog signaling has an unusual reception system consisting of two transmembrane proteins, Patched receptor and Smoothened signal transducer. Although activation of Smoothened and its downstream signal transduction have been intensively studied, less is known about how Patched receptor is regulated, and particularly how this regulation contributes to appropriate Hedgehog signal transduction. Here we identified a novel role of Smurf E3 ligase in regulating Hedgehog signaling by controlling Patched ubiquitination and turnover. Moreover, we showed that Smurf-mediated Patched ubiquitination depends on Smo activity in wing discs. Mechanistically, we found that Smo interacts with Smurf and promotes it to mediate Patched ubiquitination by targeting the K1261 site in Ptc. The further mathematic modeling analysis reveals that a bidirectional control of activation of Smo involving Smurf and Patched is important for signal-receiving cells to precisely interpret external signals, thereby maintaining Hedgehog signaling reliability. Finally, our data revealed an evolutionarily conserved role of Smurf proteins in controlling Hh signaling by targeting Ptc during development.
Author Summary
Hedgehog (Hh) signaling is a pathway renowned for its roles in controlling embryonic development and tumorigenesis. Signaling via this pathway proceeds when Hh ligands bind to the receptor Patched (Ptc), thereby preventing Ptc from inhibiting the signal transducer, Smoothened (Smo), and thus allowing Smo to accumulate on the cell surface where it becomes activated and promotes downstream signal transduction. In the absence of Hh ligands, Ptc inhibits Smo and is a key negative regulator of Hh signaling. In this study, we investigate how protein turnover of Ptc is controlled to ensure tight regulation of Hh signaling. Using Drosophila as a model system, we provide biochemical and genetic evidence to show that the E3 ligase, Smurf, directly controls Ptc protein turnover in developing wing discs. Moreover, we found that Smurf mediates Ptc degradation in a manner that depends on Smo signaling activity: activated Smo forms a complex with Smurf to preferentially promote degradation of the ligand-unbound Ptc receptor. Using mathematic modeling we reveal that the control of Smo activation by the opposing activities of Smurf and Ptc, is important for cells receiving the Hh signal to precisely interpret and relay external signals. We show that this control mechanism is also active in vertebrates with evidence that zebrafish Smurf proteins target Ptc1 protein for degradation to control late somitogenesis during zebrafish embryogenesis.
doi:10.1371/journal.pbio.1001721
PMCID: PMC3841102  PMID: 24302888
2.  COX5B Regulates MAVS-mediated Antiviral Signaling through Interaction with ATG5 and Repressing ROS Production 
PLoS Pathogens  2012;8(12):e1003086.
Innate antiviral immunity is the first line of the host defense system that rapidly detects invading viruses. Mitochondria function as platforms for innate antiviral signal transduction in mammals through the adaptor protein, MAVS. Excessive activation of MAVS-mediated antiviral signaling leads to dysfunction of mitochondria and cell apoptosis that likely causes the pathogenesis of autoimmunity. However, the mechanism of how MAVS is regulated at mitochondria remains unknown. Here we show that the Cytochrome c Oxidase (CcO) complex subunit COX5B physically interacts with MAVS and negatively regulates the MAVS-mediated antiviral pathway. Mechanistically, we find that while activation of MAVS leads to increased ROS production and COX5B expression, COX5B down-regulated MAVS signaling by repressing ROS production. Importantly, our study reveals that COX5B coordinates with the autophagy pathway to control MAVS aggregation, thereby balancing the antiviral signaling activity. Thus, our study provides novel insights into the link between mitochondrial electron transport system and the autophagy pathway in regulating innate antiviral immunity.
Author Summary
Pattern recognition receptors are vital to innate immunity. In the antiviral innate immunity, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), such as RIG-I and MDA5, sense viral RNAs through their C-terminal helicase domains, then initiate the antiviral response through interaction with the essential adaptor protein MAVS, which is located in mitochondrial outer membrane. Although cumulative studies have showed that mitochondria-associated MAVS plays an important role in antiviral signaling, much remains unknown about the mechanism of MAVS activity related to mitochondrial membrane localization. In this article we demonstrate that the CcO complex subunit COX5B negatively regulates the MAVS-mediated antiviral pathway through interaction with MAVS. At the mechanistic level, we show that COX5B inhibits MAVS-mediated antiviral pathway by suppressing ROS production, and coordinating with the autophagy pathway to control MAVS aggregation. Our data support a notion that mitochondrial electron transport system coordinates with the autophagy pathway to regulate MAVS-mediated signaling for a tight control of innate antiviral immunity.
doi:10.1371/journal.ppat.1003086
PMCID: PMC3534373  PMID: 23308066
3.  Single Endemic Genotype of Measles Virus Continuously Circulating in China for at Least 16 Years 
PLoS ONE  2012;7(4):e34401.
The incidence of measles in China from 1991 to 2008 was reviewed, and the nucleotide sequences from 1507 measles viruses (MeV) isolated during 1993 to 2008 were phylogenetically analyzed. The results showed that measles epidemics peaked approximately every 3 to 5 years with the range of measles cases detected between 56,850 and 140,048 per year. The Chinese MeV strains represented three genotypes; 1501 H1, 1 H2 and 5 A. Genotype H1 was the predominant genotype throughout China continuously circulating for at least 16 years. Genotype H1 sequences could be divided into two distinct clusters, H1a and H1b. A 4.2% average nucleotide divergence was found between the H1a and H1b clusters, and the nucleotide sequence and predicted amino acid homologies of H1a viruses were 92.3%–100% and 84.7%–100%, H1b were 97.1%–100% and 95.3%–100%, respectively. Viruses from both clusters were distributed throughout China with no apparent geographic restriction and multiple co-circulating lineages were present in many provinces. Cluster H1a and H1b viruses were co-circulating during 1993 to 2005, while no H1b viruses were detected after 2005 and the transmission of that cluster has presumably been interrupted. Analysis of the nucleotide and predicted amino acid changes in the N proteins of H1a and H1b viruses showed no evidence of selective pressure. This study investigated the genotype and cluster distribution of MeV in China over a 16-year period to establish a genetic baseline before MeV elimination in Western Pacific Region (WPR). Continuous and extensive MeV surveillance and the ability to quickly identify imported cases of measles will become more critical as measles elimination goals are achieved in China in the near future. This is the first report that a single endemic genotype of measles virus has been found to be continuously circulating in one country for at least 16 years.
doi:10.1371/journal.pone.0034401
PMCID: PMC3332093  PMID: 22532829
4.  Cell-surface localization of Pellino antagonizes Toll-mediated innate immune signalling by controlling MyD88 turnover in Drosophila 
Nature Communications  2014;5:3458.
Innate immunity mediated by Toll signalling has been extensively studied, but how Toll signalling is precisely controlled in balancing innate immune responses remains poorly understood. It was reported that the plasma membrane localization of Drosophila MyD88 is necessary for the recruitment of cytosolic adaptor Tube to the cell surface, thus contributing to Toll signalling transduction. Here we demonstrate that Drosophila Pellino functions as a negative regulator in Toll-mediated signalling. We show that Pellino accumulates at the plasma membrane upon the activation of Toll signalling in a MyD88-dependent manner. Moreover, we find that Pellino is associated with MyD88 via its CTE domain, which is necessary and sufficient to promote Pellino accumulation at the plasma membrane where it targets MyD88 for ubiquitination and degradation. Collectively, our study uncovers a mechanism by which a feedback regulatory loop involving MyD88 and Pellino controls Toll-mediated signalling, thereby maintaining homeostasis of host innate immunity.
Toll signalling activates the innate immune response; however, it remains unclear how this pathway is suppressed to avoid excessive inflammatory responses. Here, the authors report that Pellino, a RING domain-containing ubiquitin E3 ligase, is a negative regulator of Toll signalling in Drosophila.
doi:10.1038/ncomms4458
PMCID: PMC3959197  PMID: 24632597

Results 1-4 (4)