干扰素基因刺激蛋白功能调控机制的研究进展
摘要
Ⅰ型干扰素(interferon,IFN-I)在固有免疫抗病毒中发挥着关键作用,其产生与环状GMP-AMP合成酶(cyclic GMP-AMP synthase,cGAS)-干扰素基因刺激蛋白(stimulator of interferon gene,STING)信号通路对胞质内非我DNA的识别以及对下游激酶TBK1和干扰素调节因子3(interferon regulatory factor 3,IRF3)的活化密不可分。STING作为此条信号通路的核心部分,其本身的修饰和稳定性对机体能否正确有效地产生免疫应答至关重要。STING本身的功能调控机制主要分为3种:一是通过泛素化修饰促进或抑制STING信号通路;二是通过磷酸化调节STING信号通路活化的持续时间和强度;三是对STING-TBK1复合体稳定性的调节。STING功能调控机制的认识为病毒性疾病和炎症性疾病的治疗提供了新的途径。
引文
[1]Liu X,Wang Q,Pan Y,et al.Sensing and responding to cytosolic viruses invasions:An orchestra of kaleidoscopic ubiquitinations[J].Cytokine Growth Factor Rev,2015,26(3):379-387.
[2]Bernasconi R,Galli C,Kokame K,et al.Autoadaptive ERassociated degradation defines a preemptive unfolded protein response pathway[J].Mol Cell,2013,52(6):783-793.
[3]Zhong B,Zhang L,Lei C,et al.The ubiquitin ligase RNF5regulates antiviral responses by mediating degradation of the adaptor protein MITA[J].Immunity,2009,30(3):397-407.
[4]Qin Y,Zhou MT,Hu MM,et al.RNF26temporally regulates virus-triggered type I interferon induction by two distinct mechanisms[J]. PLoS Pathog, 2014, 10(9):e1004358.
[5]Wang Y,Lian Q,Yang B,et al.TRIM30alpha is a negativefeedback regulator of the intracellular DNA and DNA virustriggered response by targeting STING[J].PLoS Pathog,2015,11(6):e1005012.
[6]Xing J,Zhang A,Zhang H,et al.TRIM29promotes DNA virus infections by inhibiting innate immune response[J].Nat Commun,2017,8(1):945.
[7]Zhang J,Hu MM,Wang YY,et al.TRIM32protein modulates type I interferon induction and cellular antiviral response by targeting MITA/STING protein for K63-linked ubiquitination[J].J Biol Chem,2012,287(34):28646-28655.
[8]Tsuchida T,Zou J,Saitoh T,et al.The ubiquitin ligase TRIM56regulates innate immune responses to intracellular double-stranded DNA[J].Immunity,2010,33(5):765-776.
[9]Wang Y,Ning X,Gao P,et al.Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to regulate responses to DNA virus infection[J].Immunity,2017,46(3):393-404.
[10]Seo GJ,Kim C,Shin WJ,et al.TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing[J].Nat Commun,2018,9(1):613.
[11]Liu TF,Tang JJ,Li PS,et al.Ablation of gp78in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis[J].Cell Metab,2012,16(2):213-225.
[12]Shin YJ,Vavra U,Veit C,et al.The glycan-dependent ERAD machinery degrades topologically diverse misfolded proteins[J].Plant J,2018,94(2):246-259.
[13]Wang Q,Liu X,Cui Y,et al.The E3ubiquitin ligase AMFR and INSIG1bridge the activation of TBK1kinase by modifying the adaptor STING[J].Immunity,2014,41(6):919-933.
[14]Diner EJ,Burdette DL,Wilson SC,et al.The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING[J].Cell Rep,2013,3(5):1355-1361.
[15]Konno H,Konno K,Barber GN.Cyclic dinucleotides trigger ULK1(ATG1)phosphorylation of STING to prevent sustained innate immune signaling[J].Cell,2013,155(3):688-698.
[16]Civril F,Deimling T,de Oliveira Mann CC,et al.Structural mechanism of cytosolic DNA sensing by cGAS[J].Nature,2013,498(7454):332-337.
[17]Wu X,Yang J,Na T,et al.RIG-I and IL-6are negativefeedback regulators of STING induced by double-stranded DNA[J].PLoS One,2017,12(8):e0182961.
[18]Chen Q,Sun L,Chen ZJ.Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing[J].Nat Immunol,2016,17(10):1142-1149.
[19]Guo H,K9nig R,Deng M,et al.NLRX1sequesters STING to negatively regulate the interferon response,thereby facilitating the replication of HIV-1and DNA viruses[J].Cell Host Microbe,2016,19(4):515-528.
[20]Zhou Q,Lin H,Wang S,et al.The ER-associated protein ZDHHC1is a positive regulator of DNA virus-triggered,MITA/STING-dependent innate immune signaling[J]. Cell Host Microbe,2014,16(4):450-461.
[21]Li Y,Wilson HL,Kiss-Toth E.Regulating STING in health and disease[J].J Inflamm(Lond),2017,14:11.
[22]Wang J,Yang S,Liu L,et al.HTLV-1Tax impairs K63-linked ubiquitination of STING to evade host innate immunity[J].Virus Res,2017,232:13-21.
[23]Cao Y,Guan K,He X,et al.Yersinia YopJ negatively regulates IRF3-mediated antibacterial response through disruption of STING-mediated cytosolic DNA signaling[J].Biochim Biophys Acta,2016,1863(12):3148-3159.
[24]Liu Y,Li J,Chen J,et al.Hepatitis B virus polymerase disrupts K63-linked ubiquitination of STING to block innate cytosolic DNA-sensing pathways[J].J Virol,2015,89(4):2287-2300.
[25]Ding Q,Cao X,Lu J,et al.Hepatitis C virus NS4Bblocks the interaction of STING and TBK1to evade host innate immunity[J].J Hepatol,2013,59(1):52-58.
[26]Xia T,Konno H,Ahn J,et al.Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis[J].Cell Rep,2016,14(2):282-297.
[27]Xia T,Konno H,Barber GN.Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis[J].Cancer Res,2016,76(22):6747-6759.
[28]Bu Y,Liu F,Jia QA,et al.Decreased expression of TMEM173predicts poor prognosis in patients with hepatocellular carcinoma[J].PLoS One,2016,11(11):e0165681.
[29]Song S,Peng P,Tang Z,et al.Decreased expression of STING predicts poor prognosis in patients with gastric cancer[J].Sci Rep,2017,7:39858.
[30]Woo SR,Fuertes MB,Corrales L,et al.STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors[J].Immunity,2014,41(5):830-842.
[31]Deng L,Liang H,Xu M,et al.STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors[J].Immunity,2014,41(5):843-852.
[32]Goverman J.Autoimmune T cell responses in the central nervous system[J].Nat Rev Immunol,2009,9(6):393-407.
[33]Kemp MG,Lindsey-Boltz LA,Sancar A.UV light potentiates STING(stimulator of interferon genes)-dependent innate immune signaling through deregulation of ULK1(Unc51-like kinase 1)[J].J Biol Chem,2015,290(19):12184-12194.
[34]Pokatayev V,Hasin N,Chon H,et al.RNase H2catalytic core Aicardi-Goutieres syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice[J].J Exp Med,2016,213(3):329-336.
[35]K9nig N,Fiehn C,Wolf C,et al.Familial chilblain lupus due to a gain-of-function mutation in STING[J].Ann Rheum Dis,2017,76(2):468-472.
[36]Borba HH,Wiens A,de Souza TT,et al.Efficacy and safety of biologic therapies for systemic lupus erythematosus treatment:Systematic review and meta-analysis[J].BioDrugs,2014,28(2):211-228.
[37]Kim JE,Kim YE,Stinski MF,et al.Human cytomegalovirus IE2 86kDa protein induces STING degradation and inhibits cGAMP-mediated IFN-beta induction[J].Front Microbiol,2017,8:1854.
[2]Bernasconi R,Galli C,Kokame K,et al.Autoadaptive ERassociated degradation defines a preemptive unfolded protein response pathway[J].Mol Cell,2013,52(6):783-793.
[3]Zhong B,Zhang L,Lei C,et al.The ubiquitin ligase RNF5regulates antiviral responses by mediating degradation of the adaptor protein MITA[J].Immunity,2009,30(3):397-407.
[4]Qin Y,Zhou MT,Hu MM,et al.RNF26temporally regulates virus-triggered type I interferon induction by two distinct mechanisms[J]. PLoS Pathog, 2014, 10(9):e1004358.
[5]Wang Y,Lian Q,Yang B,et al.TRIM30alpha is a negativefeedback regulator of the intracellular DNA and DNA virustriggered response by targeting STING[J].PLoS Pathog,2015,11(6):e1005012.
[6]Xing J,Zhang A,Zhang H,et al.TRIM29promotes DNA virus infections by inhibiting innate immune response[J].Nat Commun,2017,8(1):945.
[7]Zhang J,Hu MM,Wang YY,et al.TRIM32protein modulates type I interferon induction and cellular antiviral response by targeting MITA/STING protein for K63-linked ubiquitination[J].J Biol Chem,2012,287(34):28646-28655.
[8]Tsuchida T,Zou J,Saitoh T,et al.The ubiquitin ligase TRIM56regulates innate immune responses to intracellular double-stranded DNA[J].Immunity,2010,33(5):765-776.
[9]Wang Y,Ning X,Gao P,et al.Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to regulate responses to DNA virus infection[J].Immunity,2017,46(3):393-404.
[10]Seo GJ,Kim C,Shin WJ,et al.TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing[J].Nat Commun,2018,9(1):613.
[11]Liu TF,Tang JJ,Li PS,et al.Ablation of gp78in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis[J].Cell Metab,2012,16(2):213-225.
[12]Shin YJ,Vavra U,Veit C,et al.The glycan-dependent ERAD machinery degrades topologically diverse misfolded proteins[J].Plant J,2018,94(2):246-259.
[13]Wang Q,Liu X,Cui Y,et al.The E3ubiquitin ligase AMFR and INSIG1bridge the activation of TBK1kinase by modifying the adaptor STING[J].Immunity,2014,41(6):919-933.
[14]Diner EJ,Burdette DL,Wilson SC,et al.The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING[J].Cell Rep,2013,3(5):1355-1361.
[15]Konno H,Konno K,Barber GN.Cyclic dinucleotides trigger ULK1(ATG1)phosphorylation of STING to prevent sustained innate immune signaling[J].Cell,2013,155(3):688-698.
[16]Civril F,Deimling T,de Oliveira Mann CC,et al.Structural mechanism of cytosolic DNA sensing by cGAS[J].Nature,2013,498(7454):332-337.
[17]Wu X,Yang J,Na T,et al.RIG-I and IL-6are negativefeedback regulators of STING induced by double-stranded DNA[J].PLoS One,2017,12(8):e0182961.
[18]Chen Q,Sun L,Chen ZJ.Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing[J].Nat Immunol,2016,17(10):1142-1149.
[19]Guo H,K9nig R,Deng M,et al.NLRX1sequesters STING to negatively regulate the interferon response,thereby facilitating the replication of HIV-1and DNA viruses[J].Cell Host Microbe,2016,19(4):515-528.
[20]Zhou Q,Lin H,Wang S,et al.The ER-associated protein ZDHHC1is a positive regulator of DNA virus-triggered,MITA/STING-dependent innate immune signaling[J]. Cell Host Microbe,2014,16(4):450-461.
[21]Li Y,Wilson HL,Kiss-Toth E.Regulating STING in health and disease[J].J Inflamm(Lond),2017,14:11.
[22]Wang J,Yang S,Liu L,et al.HTLV-1Tax impairs K63-linked ubiquitination of STING to evade host innate immunity[J].Virus Res,2017,232:13-21.
[23]Cao Y,Guan K,He X,et al.Yersinia YopJ negatively regulates IRF3-mediated antibacterial response through disruption of STING-mediated cytosolic DNA signaling[J].Biochim Biophys Acta,2016,1863(12):3148-3159.
[24]Liu Y,Li J,Chen J,et al.Hepatitis B virus polymerase disrupts K63-linked ubiquitination of STING to block innate cytosolic DNA-sensing pathways[J].J Virol,2015,89(4):2287-2300.
[25]Ding Q,Cao X,Lu J,et al.Hepatitis C virus NS4Bblocks the interaction of STING and TBK1to evade host innate immunity[J].J Hepatol,2013,59(1):52-58.
[26]Xia T,Konno H,Ahn J,et al.Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis[J].Cell Rep,2016,14(2):282-297.
[27]Xia T,Konno H,Barber GN.Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis[J].Cancer Res,2016,76(22):6747-6759.
[28]Bu Y,Liu F,Jia QA,et al.Decreased expression of TMEM173predicts poor prognosis in patients with hepatocellular carcinoma[J].PLoS One,2016,11(11):e0165681.
[29]Song S,Peng P,Tang Z,et al.Decreased expression of STING predicts poor prognosis in patients with gastric cancer[J].Sci Rep,2017,7:39858.
[30]Woo SR,Fuertes MB,Corrales L,et al.STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors[J].Immunity,2014,41(5):830-842.
[31]Deng L,Liang H,Xu M,et al.STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors[J].Immunity,2014,41(5):843-852.
[32]Goverman J.Autoimmune T cell responses in the central nervous system[J].Nat Rev Immunol,2009,9(6):393-407.
[33]Kemp MG,Lindsey-Boltz LA,Sancar A.UV light potentiates STING(stimulator of interferon genes)-dependent innate immune signaling through deregulation of ULK1(Unc51-like kinase 1)[J].J Biol Chem,2015,290(19):12184-12194.
[34]Pokatayev V,Hasin N,Chon H,et al.RNase H2catalytic core Aicardi-Goutieres syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice[J].J Exp Med,2016,213(3):329-336.
[35]K9nig N,Fiehn C,Wolf C,et al.Familial chilblain lupus due to a gain-of-function mutation in STING[J].Ann Rheum Dis,2017,76(2):468-472.
[36]Borba HH,Wiens A,de Souza TT,et al.Efficacy and safety of biologic therapies for systemic lupus erythematosus treatment:Systematic review and meta-analysis[J].BioDrugs,2014,28(2):211-228.
[37]Kim JE,Kim YE,Stinski MF,et al.Human cytomegalovirus IE2 86kDa protein induces STING degradation and inhibits cGAMP-mediated IFN-beta induction[J].Front Microbiol,2017,8:1854.