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author:("Fang, degu")
1.  Deleted in Breast Cancer 1 (DBC1) suppresses B cell activation through RelB and is regulated by IKKα phosphorylation 
Alternative NFκB signaling is crucial for B cell activation and immunoglobulin production, and is mainly regulated by the IKK regulatory complex. Dysregulation of alternative NFκB signaling in B cells could therefore lead to hyperactive B cells and immunoglobulin overproduction. In our previous study we found that DBC1 is a suppressor of the alternative NFκB pathway to attenuate B cell activation. In this study, we further report that loss of DBC1 results in spontaneous overproduction of immunoglobulin in mice after 10 months of age. Using a double mutant genetic model, we confirm that DBC1 suppresses B cell activation through RelB inhibition. At the molecular level, we show that DBC1 interacts with alternative NFκB members RelB and p52 through its LZ domain. In addition, phosphorylation of DBC1 at its C terminus by IKKα facilitates its interaction with RelB and IKKα, indicating that DBC1-mediated suppression of alternative NFκB is regulated by IKKα. Our results define the molecular mechanism of DBC1 inhibition of alternative NFkB activation in suppressing B cell activation.
doi:10.4049/jimmunol.1500713
PMCID: PMC4642440  PMID: 26378077
2.  The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity 
Nature Communications  2016;7:12073.
Identification of positive regulators of T-cell immunity induced during autoimmune diseases is critical for developing novel therapies. The endoplasmic reticulum resident ubiquitin ligase Hrd1 has recently emerged as a critical regulator of dendritic cell antigen presentation, but its role in T-cell immunity is unknown. Here we show that genetic deletion of Hrd1 in mice inhibits T-cell proliferation, production of IL-2, and differentiation of Th1 and Th17 cells, and consequently protects mice from experimental autoimmune encephalomyelitis. Hrd1 facilitates T-cell proliferation by the destruction of cyclin-dependent kinase inhibitor p27kip1, and deletion of p27kip1 in Hrd1-null T-cells rescues proliferative capacity but not the production of cytokines, including IL-2, IFN-γ and IL-17. T-cell expression of Hrd1 is higher in patients with multiple sclerosis than in healthy individuals, and knockdown of Hrd1 in human CD4+ T cells inhibits activation and differentiation to Th1 and Th17 cells. Our study identifies Hrd1 as a previously unappreciated positive regulator of T cells and implies that Hrd1 is a potential therapeutic target for autoimmune diseases.
Hrd1 is an E3 ubiquitin ligase involved in ER-associated degradation and MHC I turnover. Here the authors use T-cell-specific ko mice and a mouse model of multiple sclerosis to show that Hrd1 also drives pro-inflammatory T helper cell responses and contributes to pathogenesis of autoimmune disease.
doi:10.1038/ncomms12073
PMCID: PMC4947160  PMID: 27417417
3.  Cortical functional activity in patients with generalized anxiety disorder 
BMC Psychiatry  2016;16:217.
Background
The neurological correlates of Generalised Anxiety Disorder (GAD) are not well known, however there is evidence of cortical dysregulation in patients with GAD. The aim of the study was to examine cortical functional activity in different cerebral regions in patients with GAD using electroencephalogram (EEG) nonlinear analysis to evaluate its contribution of anxiety severity.
Methods
The cohorts consisted of 64 patients diagnosed with GAD as classified by the Structured Clinical Interview for the Diagnostic and Statistical Manual of the American Psychiatric Association-IV-TR. Anxiety severity was assessed using the Hamilton Rating Scale for Anxiety (HAMA) severity score, with 7 ≤ scores ≤ 17 indicating mild anxiety as A group (n = 31) and 18 and above indicating moderate-severe anxiety as B group (n = 33). Participants with clinical levels of depression symptoms were excluded. A healthy control group comprising 30 participants was matched for age and gender. Closed eyes EEGs were conducted, and between-group differences on non-linear parameter Correlation Dimension (D2) were analyzed. The association of D2 value with HAMA scores was analyzed using multiple linear stepwise regression.
Results
Compared with the control group, D2 values were increased in anxiety groups (P < .05). For those with mild anxiety, this difference occurred in the left prefrontal regions (P < .05). For those with moderate-severe anxiety, significantly greater D2 values were observed in all of the cerebral regions, especially in the left cerebral regions and right temporal lobe (P < .01). When compared with those with mild anxiety, D2 values were significantly greater for those with moderate-severe anxiety in the right temporal lobe and all left cerebral regions except for left occipital lobe (P < .05). A positive correlation was observed between D2 values and moderate-severe anxiety HAMA scores.
Conclusions
The increased D2 values were found in the majority of cerebral regions in GAD patients, especially in the left cerebral regions and the right temporal lobe. The increased GAD severity positively correlates to the D2 values in a larger number of cerebral regions. This analysis method can potentially be used as a complementary tool to examine dysfunctional cortical activity in GAD.
doi:10.1186/s12888-016-0917-3
PMCID: PMC4936202  PMID: 27388467
Psychiatry; Generalized anxiety disorder; EEG nonlinear analysis; Correlation dimension; Cortical functional activity
4.  Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism 
Molecular and Cellular Biology  2015;35(24):4121-4134.
Cyclic AMP-responsive element-binding protein 3-like 3, hepatocyte specific (CREBH), is a hepatic transcription factor that functions as a key regulator of energy homeostasis. Here, we defined a regulatory CREBH posttranslational modification process, namely, lysine-specific acetylation, and its functional involvement in fasting-induced hepatic lipid metabolism. Fasting induces CREBH acetylation in mouse livers in a time-dependent manner, and this event is critical for CREBH transcriptional activity in regulating hepatic lipid homeostasis. The histone acetyltransferase PCAF-mediated acetylation and the deacetylase sirtuin-1-mediated deacetylation coexist to maintain CREBH acetylation states under fasting conditions. Site-directed mutagenesis and functional analyses revealed that the lysine (K) residue at position 294 (K294) within the bZIP domain of the CREBH protein is the site where fasting-induced acetylation/deacetylation occurs. Introduction of the acetylation-deficient (K294R) or acetylation-mimicking (K294Q) mutation inhibited or enhanced CREBH transcriptional activity, respectively. Importantly, CREBH acetylation at lysine 294 was required for the interaction and synergy between CREBH and peroxisome proliferator-activated receptor α (PPARα) in activating their target genes upon fasting or glucagon stimulation. Introduction of the CREBH lysine 294 mutation in the liver leads to hepatic steatosis and hyperlipidemia in animals under prolonged fasting. In summary, our study reveals a molecular mechanism by which fasting or glucagon stimulation modulates lipid homeostasis through acetylation of CREBH.
doi:10.1128/MCB.00665-15
PMCID: PMC4648819  PMID: 26438600
5.  IRE1α is an endogenous substrate of endoplasmic reticulum-associated degradation 
Nature cell biology  2015;17(12):1546-1555.
Endoplasmic reticulum (ER)-associated degradation (ERAD) represents a principle quality control mechanism to clear misfolded proteins in the ER; however its physiological significance and the nature of endogenous ERAD substrates remain largely unexplored. Here we discover that IRE1α, the sensor of unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. ERAD-mediated IRE1α degradation occurs under basal conditions in a BiP-dependent manner, requires both intramembrane hydrophilic residues of IRE1α and lectin protein OS9, and is attenuated by ER stress. ERAD deficiency causes IRE1α protein stabilization, accumulation and mild activation both in vitro and in vivo. Although enterocyte-specific Sel1L-knockout mice (Sel1LΔIEC) are viable and appear normal, they are highly susceptible to experimental colitis and inflammation-associated dysbiosis, in an IRE1α-dependent but CHOP-independent manner. Hence, Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1α signaling in vivo by managing its protein turnover.
doi:10.1038/ncb3266
PMCID: PMC4670240  PMID: 26551274
ER; Sel1L; Hrd1; ERAD; UPR; intestinal epithelium; inflammation; colitis
6.  Ubiquitin-specific protease 22 is a deubiquitinase of CCNB1 
Cell discovery  2015;1:15028.
The elevated level of CCNB1 indicates more aggressive cancer and poor prognosis. However, the factors that cause CCNB1 upregulation remain enigmatic. Herein, we identify USP22 as a CCNB1 interactor and discover that both USP22 and CCNB1 are dramatically elevated with a strong positive correlation in colon cancer tissues. USP22 stabilizes CCNB1 by antagonizing proteasome-mediated degradation in a cell cycle-specific manner. Phosphorylation of USP22 by CDK1 enhances its activity in deubiquitinating CCNB1. The ubiquitin ligase anaphase-promoting complex (APC/C) targets USP22 for degradation by using the substrate adapter CDC20 during cell exit from M phase, presumably allowing CCNB1 degradation. Finally, we discover that USP22 knockdown leads to slower cell growth and reduced tumor size. Our study demonstrates that USP22 is a CCNB1 deubiquitinase, suggesting that targeting USP22 might be an effective approach to treat cancers with elevated CCNB1 expression.
doi:10.1038/celldisc.2015.28
PMCID: PMC4809424  PMID: 27030811
USP22; CCNB1; APC8; cell cycle; tumorigenesis
7.  Stem cell-derived tissue-associated regulatory T cells ameliorate the development of autoimmunity 
Scientific Reports  2016;6:20588.
Pluripotent stem cells (PSCs) have the potential to produce almost all of the cells in the body, including regulatory T cells (Tregs). However, the exact conditions required for the development of antigen (Ag)-specific Tregs from PSCs (i.e., PSC-Tregs) are not well delineated. Ag-specific PSC-Tregs can be tissue/organ-associated and migrate to local inflamed tissues/organs to suppress the autoimmune response after adoptive transfer, thereby avoiding potential overall immunosuppression from non-specific Tregs. In this study, we developed a new approach to generate functional Ag-specific Tregs from induced PSCs (iPSCs), i.e., iPSC-Tregs, which had the ability to generate an Ag-specific immunosuppressive response in a murine model of arthritis. We retrovirally transduced murine iPSCs with a construct containing genes of Ag-specific T cell receptor (TCR) and the transcriptional factor FoxP3. We differentiated the iPSCs into Ag-specific iPSC-Tregs using in vitro or in vivo Notch signaling, and demonstrated that adoptive transfer of such Tregs dramatically suppressed autoimmunity in a well-established Ag-induced arthritis model, including the inflammation, joint destruction, cartilage prostaglandin depletion, osteoclast activity, and Th17 production. Our results indicate that PSCs can be used to develop Ag-specific Tregs, which have a therapeutic potential for Treg-based therapies of autoimmune disorders.
doi:10.1038/srep20588
PMCID: PMC4742827  PMID: 26846186
8.  Host miR-155 promotes tumor growth through a myeloid-derived suppressor cell-dependent mechanism 
Cancer research  2014;75(3):519-531.
miR-155 is a regulator of immune cell development and function that is generally thought to be immunostimulatory. However, we report here that genetic ablation of miR-155 renders mice resistant to chemical carcinogenesis and the growth of several transplanted tumors, suggesting that miR-155 functions in immunosuppression and tumor promotion. Host miR-155 deficiency promoted overall antitumor immunity despite the finding of defective responses of miR-155-deficient dendritic cells and antitumor T cells. Further analysis of immune cell compartments revealed that miR-155 regulated the accumulation of functional myeloid-derived suppressive cells (MDSC) in the tumor microenvironment. Specifically, miR-155 mediated MDSC suppressor activity through at least two mechanisms, including SOCS1 repression and a reduced ability to license the generation of CD4+Foxp3+ regulatory T cells (Treg). Importantly, we demonstrated that miR-155 expression was required for MDSC to facilitate tumor growth. Thus, our results revealed a contextual function for miR-155 in antitumor immunity, with a role in MDSC support that appears to dominate in tumor-bearing hosts. Overall, the balance of these cellular effects appears to be a root determinant of whether miR-155 promotes or inhibits tumor growth.
doi:10.1158/0008-5472.CAN-14-2331
PMCID: PMC4315710  PMID: 25502838
9.  C-Myc regulation by costimulatory signals modulates the generation of CD8+ memory T cells during viral infection 
Open Biology  2016;6(1):150208.
The signalling mechanisms of costimulation in the development of memory T cells remain to be clarified. Here, we show that the transcription factor c-Myc in CD8+ T cells is controlled by costimulatory molecules, which modulates the development of memory CD8+ T cells. C-Myc expression was dramatically reduced in Cd28−/− or Ox40−/− memory CD8+ T cells, and c-Myc over-expression substantially reversed the defects in the development of T-cell memory following viral infection. C-Myc regulated the expression of survivin, an inhibitor of apoptosis, which promoted the generation of virus-specific memory CD8+ T cells. Moreover, over-expression of survivin with bcl-xL, a downstream molecule of NF-κB and intracellular target of costimulation that controls survival, in Cd28−/− or Ox40−/− CD8+ T cells, reversed the defects in the generation of memory T cells in response to viral infection. These results identify c-Myc as a key controller of memory CD8+ T cells from costimulatory signals.
doi:10.1098/rsob.150208
PMCID: PMC4736826  PMID: 26791245
c-Myc; costimulation; CD8+ T cells; memory; viral infection
10.  Deleted in Breast Cancer 1 (DBC1) is a Suppressor of B cell Activation by Negatively Regulating Alternative NF-κB Transcriptional Activity 
CD40 and BAFF receptor (BAFFR) signaling plays important roles in B cell proliferation and immunoglobulin production. In this study we found that B cells from mice with deletion of Dbc1 gene (Dbc1−/−) show elevated proliferation, and IgG1 and IgA production upon in vitro CD40 and BAFF, but not BCR and LPS stimulation, indicating that DBC1 inhibits CD40/BAFF-mediated B cell activation in a cell-intrinsic manner. Microarray analysis and Chromatin Immunoprecipitation (ChIP) experiments reveal that DBC1 inhibits B cell function by selectively suppressing the transcriptional activity of alternative NF-κB members RelB and p52 upon CD40 stimulation. As a result, when immunized with Nitrophenylated-Keyhole Limpet Hemocyanin (NP-KLH), Dbc1−/− mice produce significantly increased levels of germinal center B cells, plasma cells, as well as antigen-specific immunoglobulin. Finally, loss of DBC1 in mice leads to higher susceptibility to Experimental Autoimmune Myasthenia Gravis (EAMG). Our study identifies DBC1 as a novel regulator of B cell activation by suppressing the alternative NF-κB pathway.
doi:10.4049/jimmunol.1401798
PMCID: PMC4259264  PMID: 25362179
11.  Ubiquitin-specific protease 22 is a deubiquitinase of CCNB1 
Cell Discovery  2015;1:15028-.
The elevated level of CCNB1 indicates more aggressive cancer and poor prognosis. However, the factors that cause CCNB1 upregulation remain enigmatic. Herein, we identify USP22 as a CCNB1 interactor and discover that both USP22 and CCNB1 are dramatically elevated with a strong positive correlation in colon cancer tissues. USP22 stabilizes CCNB1 by antagonizing proteasome-mediated degradation in a cell cycle-specific manner. Phosphorylation of USP22 by CDK1 enhances its activity in deubiquitinating CCNB1. The ubiquitin ligase anaphase-promoting complex (APC/C) targets USP22 for degradation by using the substrate adapter CDC20 during cell exit from M phase, presumably allowing CCNB1 degradation. Finally, we discover that USP22 knockdown leads to slower cell growth and reduced tumor size. Our study demonstrates that USP22 is a CCNB1 deubiquitinase, suggesting that targeting USP22 might be an effective approach to treat cancers with elevated CCNB1 expression.
doi:10.1038/celldisc.2015.28
PMCID: PMC4809424  PMID: 27030811
USP22; CCNB1; APC8; cell cycle; tumorigenesis
12.  A Hrd way for MHC-II expression 
Oncotarget  2015;6(26):21767-21768.
PMCID: PMC4673110  PMID: 26312567
Immunology and Microbiology Section; Immune response; Immunity
13.  A novel ER–microtubule-binding protein, ERLIN2, stabilizes Cyclin B1 and regulates cell cycle progression 
Cell Discovery  2015;1:15024-.
The gene encoding endoplasmic reticulum (ER) lipid raft-associated protein 2 (ERLIN2) is amplified in human breast cancers. ERLIN2 gene mutations were also found to be associated with human childhood progressive motor neuron diseases. Yet, an understanding of the physiological function and mechanism for ERLIN2 remains elusive. In this study, we reveal that ERLIN2 is a spatially and temporally regulated ER–microtubule-binding protein that has an important role in cell cycle progression by interacting with and stabilizing the mitosis-promoting factors. Whereas ERLIN2 is highly expressed in aggressive human breast cancers, during normal development ERLIN2 is expressed at the postnatal stage and becomes undetectable in adulthood. ERLIN2 interacts with the microtubule component α-tubulin, and this interaction is maximal during the cell cycle G2/M phase where ERLIN2 simultaneously interacts with the mitosis-promoting complex Cyclin B1/Cdk1. ERLIN2 facilitates K63-linked ubiquitination and stabilization of Cyclin B1 protein in G2/M phase. Downregulation of ERLIN2 results in cell cycle arrest, represses breast cancer proliferation and malignancy and increases sensitivity of breast cancer cells to anticancer drugs. In summary, our study revealed a novel ER–microtubule-binding protein, ERLIN2, which interacts with and stabilizes mitosis-promoting factors to regulate cell cycle progression associated with human breast cancer malignancy.
doi:10.1038/celldisc.2015.24
PMCID: PMC4860859  PMID: 27462423
breast cancer; Cyclin B1; endoplasmic reticulum; ER lipid raft protein; microtubule; mitosis
14.  CD11c-mediated Deletion of Flip Promotes Autoreactivity and Inflammatory Arthritis 
Nature communications  2015;6:7086.
Dendritic cells (DCs) are critical for immune homeostasis. To target DCs, we generated a mouse line with Flip deficiency in cells that express cre under the CD11c-promoter (CD11c-Flip-KO). CD11c-Flip-KO mice spontaneously develop erosive, inflammatory arthritis, resembling rheumatoid arthritis, which is dramatically reduced when these mice are crossed with Rag−/− mice. The CD8α+ DC subset is significantly reduced, along with alterations in NK cells and macrophages. Autoreactive CD4+ T cells and autoantibodies specific for joint tissue are present and arthritis severity correlates with the number of autoreactive CD4+ T cells and plasmablasts in the joint draining lymph nodes. Reduced T regulatory cells (Tregs) inversely correlate with arthritis severity, and the transfer of Tregs ameliorates arthritis. This KO line identifies a model that will permit in depth interrogation of the pathogenesis of rheumatoid arthritis, including the role of CD8α+ DCs and other cells of the immune system.
doi:10.1038/ncomms8086
PMCID: PMC4429912  PMID: 25963626
15.  Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation 
The Journal of Experimental Medicine  2014;211(12):2467-2479.
Yang et al. demonstrate that Hrd1 plays an important role in DC induction of CD4 T cell immunity. The underlying mechanism involves the ability of Hrd1 to ubiquitinate and degrade BLIMP-1, thus releasing CIITA from transcriptional repression and promoting MHCII expression. As a consequence, Hrd1−/− DCs protect mice from MOG-induced experimental autoimmune encephalomyelitis.
The ubiquitin pathway plays critical roles in antigen presentation. However, the ubiquitin ligases that regulate MHC gene transcription remain unidentified. We showed that the ubiquitin ligase Hrd1, expression of which is induced by Toll-like receptor (TLR) stimulation, is required for MHC-II but not MHC-I transcription in dendritic cells (DCs). Targeted Hrd1 gene deletion in DCs diminished MHC-II expression. As a consequence, Hrd1-null DCs failed to prime CD4+ T cells without affecting the activation of CD8+ T cells. Hrd1 catalyzed ubiquitination and degradation of the transcriptional suppressor B lymphocyte–induced maturation protein 1 (BLIMP1) to promote MHC-II expression. Genetic suppression of Hrd1 function in DCs protected mice from myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis (EAE). We identified Hrd1-mediated BLIMP1 ubiquitination as a previously unknown mechanism in programming DC for CD4+ T cell activation during inflammation.
doi:10.1084/jem.20140283
PMCID: PMC4235642  PMID: 25366967
16.  CD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis 
Nature Communications  2015;6:7086.
Dendritic cells (DCs) are critical for immune homeostasis. To target DCs, we generated a mouse line with Flip deficiency in cells that express cre under the CD11c promoter (CD11c-Flip-KO). CD11c-Flip-KO mice spontaneously develop erosive, inflammatory arthritis, resembling rheumatoid arthritis, which is dramatically reduced when these mice are crossed with Rag−/− mice. The CD8α+ DC subset is significantly reduced, along with alterations in NK cells and macrophages. Autoreactive CD4+ T cells and autoantibodies specific for joint tissue are present, and arthritis severity correlates with the number of autoreactive CD4+ T cells and plasmablasts in the joint-draining lymph nodes. Reduced T regulatory cells (Tregs) inversely correlate with arthritis severity, and the transfer of Tregs ameliorates arthritis. This KO line identifies a model that will permit in depth interrogation of the pathogenesis of rheumatoid arthritis, including the role of CD8α+ DCs and other cells of the immune system.
Dendritic cells are critical for initiation of immune responses and for induction of tolerance. Here the authors show that deletion of survival factor c-flip in CD11c-expressing cells subset perturbs CD8a+ dendritic cell, NK and macrophage pools, and leads to development of autoimmune arthritis.
doi:10.1038/ncomms8086
PMCID: PMC4429912  PMID: 25963626
17.  HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation 
Neuropsychopharmacology  2014;39(6):1469-1478.
Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psychopathological conditions, including psychosis and the behavioral disturbances associated with dementia. However, clinical experience suggests that these drugs may be less efficacious in the elderly individuals than in the young. Recent studies suggest that aging may be associated with epigenetic changes and that valproic acid (VPA), a histone deacetylase inhibitor, may reverse such changes. However, it is not yet known whether HDAC inhibitors can modulate age-related epigenetic changes that may impact antipsychotic drug action. In this study, we analyzed conditioned avoidance response (CAR) and c-Fos expression patterns to elucidate the effect of HDAC inhibitors VPA and entinostat (MS-275) on behavioral and molecular markers of the effects of haloperidol (HAL) in aged mice. Our results showed that HAL administration failed to suppress the avoidance response during the CAR test, suggesting an age-related decrease in drug efficacy. In addition, HAL-induced c-Fos expression in the nucleus accumbens shell and prefrontal cortex was significantly lower in aged mice as compared with young mice. Pretreatment with VPA and MS-275 significantly improved HAL effects on the CAR test in aged mice. Also, VPA and MS-275 pretreatment restored HAL-induced increases in c-Fos expression in the nucleus accumbens shell and prefrontal cortex of aged mice to levels comparable with those observed in young mice. Lastly, but most importantly, increases in c-Fos expression and HAL efficacy in the CAR test of the HAL+VPA and HAL+MS-275 groups were correlated with elevated histone acetylation at the c-fos promoter region in aged mice. These findings suggest that pretreatment with VPA or MS-275 increases the behavioral and molecular effects of HAL in aged mice and that these effects occur via modulation of age-related histone hypoacetylation in the nucleus accumbens shell and prefrontal cortex.
doi:10.1038/npp.2013.346
PMCID: PMC3988551  PMID: 24366052
aging; geriatrics; molecular & cellular neurobiology; pharmacogenetics; pharmacogenomics; schizophrenia; antipsychotics; aging; epigenetics; antipsychotics; valproic acid; haloperidol; entinostat; aging; haloperidol; epigenetics; valproic acid (VPA); entinostat (MS-275); mice
18.  Icariin Induces Synoviolin Expression through NFE2L1 to Protect Neurons from ER Stress-Induced Apoptosis 
PLoS ONE  2015;10(3):e0119955.
By suppressing neuronal apoptosis, Icariin is a potential therapeutic drug for neuronal degenerative diseases. The molecular mechanisms of Icariin anti-apoptotic functions are still largely unclear. In this report, we found that Icariin induces the expression of Synoviolin, an endoplasmic reticulum (ER)-anchoring E3 ubiquitin ligase that functions as a suppressor of ER stress-induced apoptosis. The nuclear factor erythroid 2-related factor 1 (NFE2L1) is responsible for Icariin-mediated Synoviolin gene expression. Mutation of the NFE2L1-binding sites in a distal region of the Synoviolin promoter abolished Icariin-induced Synoviolin promoter activity, and knockdown of NFE2L1 expression prevented Icariin-stimulated Synoviolin expression. More importantly, Icariin protected ER stress-induced apoptosis of PC12 cells in a Synoviolin-dependent manner. Therefore, our study reveals Icariin-induced Synoviolin expression through NFE2L1 as a previously unappreciated molecular mechanism underlying the neuronal protective function of Icariin.
doi:10.1371/journal.pone.0119955
PMCID: PMC4373914  PMID: 25806530
19.  USP10 Antagonizes c-Myc Transcriptional Activation through SIRT6 Stabilization to Suppress Tumor Formation 
Cell reports  2013;5(6):1639-1649.
The reduced protein expression of SIRT6 tumor suppressor is involved in tumorigenesis. The molecular mechanisms underlying SIRT6 protein downregulation in human cancers remain unknown. Using a proteomic approach, we have identified the ubiquitin-specific peptidase USP10, another tumor suppressor, as one of the SIRT6-interacting proteins. USP10 suppresses SIRT6 ubiquitination to protect SIRT6 from proteasomal degradation. USP10 antagonizes the transcriptional activity of the c-Myc oncogene through SIRT6, as well as p53, to inhibit cell cycle progression, cancer cell growth, and tumor formation. To support this conclusion, we detected significant reductions in both USP10 and SIRT6 protein expression in human colon cancers. Our study discovered crosstalk between two tumor-suppressive genes in regulating cell cycle progression and proliferation and showed that dysregulated USP10 function promotes tumorigenesis through SIRT6 degradation.
doi:10.1016/j.celrep.2013.11.029
PMCID: PMC4007576  PMID: 24332849
20.  Tumor protein translationally controlled 1 is a p53 target gene that promotes cell survival 
Cell Cycle  2013;12(14):2321-2328.
Tumor suppressor p53 maintains genome stability by differentially activating target genes that control diverse cellular responses, such as the antioxidant response, cell cycle arrest and apoptosis. Despite the fact that many p53 downstream genes have been well characterized, novel p53 target genes are continuously being identified. Here, we report that Tpt1 is a direct target gene of p53. We found that p53 upregulates the transcription of Tpt1 and identified a p53-responsive element in the promoter of the mouse Tpt1 gene. Furthermore, p53-dependent induction of Tpt1 was able to reduce oxidative stress, minimize apoptosis, and promote cell survival in response to H2O2 challenge. In addition, a positive correlation between the expression of p53 and Tpt1 only existed in normal lung tissues, not in lung tumors. Such positive correlation was also found in lung cell lines that contain wild-type p53, but not mutated p53. Based on the important role of Tpt1 in cancer development, chemoresistance, and cancer reversion, identification of Tpt1 as a direct target gene of p53 not only adds to the complexity of the p53 network, but may also open up a new avenue for cancer prevention and intervention.
doi:10.4161/cc.25404
PMCID: PMC3755082  PMID: 24067374
p53; Tpt1; TCTP; cancer
21.  USP15 negatively regulates Nrf2 through deubiquitination of Keap1 
Molecular cell  2013;51(1):68-79.
Summary
Nrf2 is a master regulator of the antioxidant response. Under basal conditions Nrf2 is polyubiquitinated by the Keap1-Cul3-E3 ligase and degraded by the 26S-proteasome. In response to Nrf2 inducers there is a switch in polyubiquitination from Nrf2 to Keap1. Currently, regulation of the Nrf2-Keap1 pathway by ubiquitination is largely understood. However, the mechanism responsible for removal of ubiquitin conjugated to Nrf2 or Keap1 remains unknown. Here we report that the deubiquitinating enzyme, USP15, specifically deubiquitinates Keap1, which suppresses the Nrf2 pathway. We demonstrated that deubiquitinated-Keap1 incorporates into the Keap1-Cul3-E3 ligase complex more efficiently, enhancing the complex stability and enzymatic activity. Consequently, there is an increase in Nrf2 protein degradation and a reduction in Nrf2 target gene expression. Furthermore, USP15-siRNA enhances chemoresistance of cells through upregulation of Nrf2. These findings further our understanding of how the Nrf2-Keap1 pathway is regulated, which is imperative in targeting this pathway for chemoprevention or chemotherapy.
doi:10.1016/j.molcel.2013.04.022
PMCID: PMC3732832  PMID: 23727018
Nrf2; Keap1; USP15; Cul3; ubiquitination; deubiquitination; antioxidant response; chemoresistance
22.  Transgenic expression of survivin compensates for OX40-deficiency in driving Th2 development and allergic inflammation 
European journal of immunology  2013;43(7):10.1002/eji.201243081.
Summary
Survivin, an inhibitor of apoptosis family molecule, has been proposed as a crucial intermediate in the signaling pathways leading to T-cell development, proliferation, and expansion. However, the importance of survivin to T-cell-driven inflammatory responses has not been demonstrated. Here, we show that survivin transgenic mice exhibit an increased antigen-driven Th2 lung inflammation and that constitutive expression of survivin reversed the defective lung inflammation even in the absence of OX40 costimulation. We found that OX40-deficient mice were compromised in generating Th2 cells, airway eosinophilia, and IgE responses. In contrast, OX40-deficient/survivin transgenic mice generated normal Th2 responses and exhibited strong lung inflammation. These results suggested that OX40 costimulation crucially engaged survivin during antigen-mediated Th2 responses. These findings also promote the notion that OX40 costimulation regulated allergic responses or lung inflammation by targeting survivin thereby enhancing T-cell proliferation and resulting in more differentiated Th2 cells in the allergic inflammatory response.
doi:10.1002/eji.201243081
PMCID: PMC3876962  PMID: 23616302
costimulation; lung inflammation; murine model; survivin; Th2 cells
23.  The Class III Histone Deacetylase Sirtuin 1 in Immune Suppression and Its Therapeutic Potential in Rheumatoid Arthritis 
Rheumatoid arthritis (RA) is a chronic debilitating disease of the joints. Both the innate and adaptive immune responses participate in the development and progression of RA. While several therapeutic reagents, such as TNF-α agonists, have been successfully developed for the clinical use in the treatment of RA, more than half of the patients do not respond to anti-TNF therapy. Therefore, new therapeutic reagents are needed. Recent studies have shown that sirtuin 1 (Sirt1), a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, is a critical negative regulator of both the innate and adaptive immune response in mice, and its altered functions are likely to be involved in autoimmune diseases. Small molecules that modulate Sirt1 functions are potential therapeutic reagents for autoimmune inflammatory diseases. This review highlights the role of Sirt1 in immune regulation and RA.
doi:10.1016/j.jgg.2013.04.001
PMCID: PMC4007159  PMID: 23876775
Rheumatoid arthritis; Sirt1; Epigenetic
24.  Does Nrf2 Contribute to p53-Mediated Control of Cell Survival and Death? 
Antioxidants & Redox Signaling  2012;17(12):1670-1675.
Abstract
In response to oxidative stress, the transcription factor Nrf2 is upregulated and controls activation of many genes that work in concert to defend cells from damages and to maintain cellular redox homeostasis. p53 has been regarded as the guardian of the genome through its pro-oxidant and antioxidant functions. Under low levels of reactive oxygen species (ROS), “normal” amounts of p53 upregulates expression of antioxidant genes, protecting macromolecules from ROS-induced damage. However, at high levels or extended exposure of ROS, p53 expression is enhanced, activating pro-oxidant genes and resulting in p53-dependent apoptosis. We observed a two-phase Nrf2 expression controlled by p53. (i) The induction phase: when p53 expression is relatively low, p53 enhances the protein level of Nrf2 and its target genes to promote cell survival in a p21-dependent manner. (ii) The repression phase: when p53 expression is high, the Nrf2-mediated survival response is inhibited by p53. Our observation leads to the hypothesis that the p53-mediated biphasic regulation of Nrf2 may be key for the tumor-suppressor function of p53 by coordinating cell survival and death pathways. Antioxid. Redox Signal. 17, 1670–1675.
doi:10.1089/ars.2012.4674
PMCID: PMC3474188  PMID: 22559194
25.  Resveratrol Inhibits CD4+ T Cell Activation by Enhancing the Expression and Activity of Sirt1 
PLoS ONE  2013;8(9):e75139.
Resveratrol, a natural polyphenol compound, has broad effects on critical events, including inflammation, oxidation, cancer and aging. However, the function and molecular mechanisms of resveratrol on T cell activation are controversial. In the present study, we found that resveratrol significantly inhibits the activation and cytokine production of T cells in vitro and in vivo. Sirt1 expression was up-regulated in resveratrol-treated T cells. Once Sirt1 was down-regulated in the T cells, the resveratrol-induced inhibition of T cell activation noticeably diminished. The acetylation of c-Jun decreased and its translocation was impeded in the resveratrol-treated T cells. The incidence and severity of collagen-induced arthritis in the resveratrol-treated mice were considerably reduced.
doi:10.1371/journal.pone.0075139
PMCID: PMC3779207  PMID: 24073240

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