接头蛋白STING介导信号通路在抗病毒感染中的研究进展
摘要
干扰素基因刺激蛋白(stimulator of interferon gene,STING)是一种介导胞内DNA诱导固有免疫应答的重要接头蛋白,在机体抗病毒免疫反应中起关键作用。宿主细胞通过模式识别受体(pattern recognition receptor,PRR)识别入侵病原体的DNA,将信号传递给STING,导致TANK连接激酶1(TANK-binding kinase 1,TBK1)和干扰素调控因子3(interferon regulatory factor 3,IRF3)磷酸化,从而促进Ⅰ型IFN的上调表达,进而抑制病毒复制。文章介绍了STING分子的结构、转导通路以及分子调控机制,重点概述STING介导的信号通路在抗病毒感染中的作用以及病毒对该信号通路的调控机制,以期为抗病毒药物的研究提供新的靶点和思路。
引文
[1] 熊思东. 抗病毒感染的固有免疫机制[J]. 现代免疫学, 2011, 31(3): 179-180.
[2] Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling[J]. Nature, 2008, 455(7213): 674-678.
[3] Zhong B, Yang Y, Li S, et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation[J]. Immunity, 2008, 29(4): 538-550.
[4] Jin L, Waterman PM, Jonscher KR, et al. MPYS, a novel membrane tetraspanner, is associated with major histocompatibility complex class Ⅱ and mediates transduction of apoptotic signals[J]. Mol Cell Biol, 2008, 28(16): 5014-5026.
[5] Sun W, Li Y, Chen L, et al. ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization[J]. Proc Natl Acad Sci U S A, 2009, 106(21): 8653-8658.
[6] Ouyang S, Song X, Wang Y, et al. Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding[J]. Immunity, 2012, 36(6): 1073-1086.
[7] Gao P, Ascano M, Zillinger T, et al. Structure-function analysis of STING activation by c[G(2',5')pA(3',5')p] and targeting by antiviral DMXAA[J]. Cell, 2013, 154(4): 748-762.
[8] Tanaka Y, Chen ZJ. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway[J]. Sci Signal, 2012, 5(214): ra20.
[9] Zhong B, Zhang L, Lei C, et al. The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA[J]. Immunity, 2009, 30(3): 397-407.
[10] Bhat N, Fitzgerald KA. Recognition of cytosolic DNA by cGAS and other STING-dependent sensors: Highlights[J]. Eur J Immunol, 2014, 44(3): 634-640.
[11] Tsuchida T, Zou J, Saitoh T, et al. The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA[J]. Immunity, 2010, 33(5): 765-776.
[12] Cui H, Liu Y, Huang Y. Roles of TRIM32 in corneal epithelial cells after infection with herpes simplex virus[J]. Int J Exp Cell Physiol Biochem Pharmacol, 2017, 43(2): 801-811.
[13] Sun L, Wu J, Du F, et al. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type Ⅰ interferon pathway[J]. Science, 2013, 339(6121): 786-791.
[14] Zhang X, Shi H, Wu J, et al. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING[J]. Mol Cell, 2013, 51(2): 226-235.
[15] Qiu H, Fan Y, Joyee AG, et al. Type Ⅰ IFNs enhance susceptibility to chlamydia muridarum lung infection by enhancing apoptosis of local macrophages[J]. J Immunol, 2008, 181(3): 2092-2102.
[16] Barker JR, Koestler BJ, Carpenter VK, et al. STING-dependent recognition of cyclic di-AMP mediates type Ⅰ interferon responses during chlamydia trachomatis infection[J]. MBio, 2013, 4(3): e00018-13.
[17] Kim S, Li L, Maliga Z, et al. Anticancer flavonoids are mouse-selective STING agonists[J]. ACS Chem Biol, 2013, 8(7): 1396-1401.
[18] Zhang H, Han MJ, Tao J, et al. Rat and human STINGs profile similarly towards anticancer/antiviral compounds[J]. Sci Rep, 2015, 5: 18035.
[19] Corrales L, Glickman LH, Mcwhirter SM, et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity[J]. Cell Rep, 2015, 11(7): 1018-1030.
[20] Fu J, Kanne DB, Leong M, et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade[J]. Sci Transl Med, 2015, 7(283): 283ra52.
[21] Baird JR, Friedman D, Cottam B, et al. Radiotherapy combined with novel STING-targeting oligonucleotides results in regression of established tumors[J]. Cancer Res, 2016, 76(1): 50-61.
[22] Watson RO, Manzanillo PS, Cox JS. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway[J]. Cell, 2012, 150(4): 803-815.
[23] Watson RO, Bell SL, Macduff DA, et al. The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type Ⅰ interferons and activate autophagy[J]. Cell Host Microbe, 2015, 17(6): 811-819.
[24] Moretti J, Roy S, Bozec D, et al. STING senses microbial viability to orchestrate stress-mediated autophagy of the endoplasmic reticulum[J]. Cell, 2017, 171(4): 809-823.e13.
[25] Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type Ⅰ interferon-dependent innate immunity[J]. Nature, 2009, 461(7265): 788-792.
[26] Lio CW, McDonald B, Takahashi M, et al. cGAS-STING signaling regulates initial innate control of cytomegalovirus infection[J]. J Virol, 2016, 90(17): 7789-7797.
[27] Ma Z, Damania B. The cGAS-STING defense pathway and its counteraction by viruses[J]. Cell Host Microbe, 2016, 19(2): 150-158.
[28] Schoggins JW, Macduff DA, Imanaka N, et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity[J]. Nature, 2014, 505(7485): 691-695.
[29] Li XD, Wu J, Gao D, et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects[J]. Science, 2013, 341(6152): 1390-1394.
[30] Ma Z, Jacobs SR, West JA, et al. Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses[J]. Proc Natl Acad Sci U S A, 2015, 112(31): E4306-E4315.
[31] Paijo J, Doring M, Spanier J, et al. cGAS senses human cytomegalovirus and induces type Ⅰ interferon responses in human monocyte-derived cells[J].PLoS Pathog, 2016, 12(4): e1005546.
[32] Anghelina D, Lam E, Falck-Pederson E. Diminished innate antiviral response to adenovirus vectors in cGAS/STING-deficient mice minimally impacts adaptive immunity[J]. J Virol, 2016, 90(13): 5915-5927.
[33] Reinert LS, Lopusna K, Winther H, et al. Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS[J]. Nat Commun, 2016, 7: 13348.
[34] Holm CK, Rahbek SH, Gad HH, et al. Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses[J]. Nat Commun, 2016, 7: 10680.
[35] Zevini A, Olagnier D, Hiscott J. Crosstalk between cytoplasmic RIG-Ⅰ and STING sensing pathways[J]. Trends Immunol, 2017, 38(3): 194-205.
[36] Barber GN. STING: Infection, inflammation and cancer[J]. Nat Rev Immunol, 2015, 15(12): 760-770.
[37] Aguirre S, Maestre AM, Pagni S, et al. DENV inhibits type Ⅰ IFN production in infected cells by cleaving human STING[J]. PLoS Pathog, 2012, 8(10): e1002934.
[38] Ding Q, Cao X, Lu J, et al. Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity[J]. J Hepatol, 2013, 59(1): 52-58.
[39] Nitta S, Sakamoto N, Nakagawa M, et al. Hepatitis C virus NS4B protein targets STING and abrogates RIG-Ⅰ-mediated type Ⅰ interferon-dependent innate immunity[J]. Hepatology, 2013, 57(1): 46-58.
[40] Li Y, Li C, Xue P, et al. ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response[J]. Proc Natl Acad Sci, 2009, 106(19): 7945-7950.
[41] Abbas YM, Laudenbach BT, Martinez-Montero S, et al. Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2'-O methylations[J]. Proc Natl Acad Sci U S A, 2017, 114(11): E2106-E2115.
[42] Kumar P, Sweeney TR, Skabkin MA, et al. Inhibition of translation by IFIT family members is determined by their ability to interact selectively with the 5'-terminal regions of cap0-, cap1- and 5'ppp-mRNAs[J]. Nucleic Acids Res, 2014, 42(5): 3228-3245.
[43] Xing Y, Chen J, Tu J, et al. The papain-like protease of porcine epidemic diarrhea virus negatively regulates type Ⅰ interferon pathway by acting as a viral deubiquitinase[J]. J Gen Virol, 2013, 94(Pt7): 1554-1567.
[44] Clementz MA, Chen Z, Banach BS, et al. Deubiquitinating and interferon antagonism activities of coronavirus papain-like proteases[J]. J Virol, 2010, 84(9): 4619-4629.
[45] Christensen MH, Jensen SB, Miettinen JJ, et al. HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type Ⅰ IFN expression[J]. EMBO J, 2016, 35(13): 1385-1399.
[46] 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.
[47] He J, Hao R, Liu D, et al. Inhibition of hepatitis B virus replication by activation of the cGAS-STING pathway[J]. J Gen Virol, 2016, 97(12): 3368-3378.
[2] Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling[J]. Nature, 2008, 455(7213): 674-678.
[3] Zhong B, Yang Y, Li S, et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation[J]. Immunity, 2008, 29(4): 538-550.
[4] Jin L, Waterman PM, Jonscher KR, et al. MPYS, a novel membrane tetraspanner, is associated with major histocompatibility complex class Ⅱ and mediates transduction of apoptotic signals[J]. Mol Cell Biol, 2008, 28(16): 5014-5026.
[5] Sun W, Li Y, Chen L, et al. ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization[J]. Proc Natl Acad Sci U S A, 2009, 106(21): 8653-8658.
[6] Ouyang S, Song X, Wang Y, et al. Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding[J]. Immunity, 2012, 36(6): 1073-1086.
[7] Gao P, Ascano M, Zillinger T, et al. Structure-function analysis of STING activation by c[G(2',5')pA(3',5')p] and targeting by antiviral DMXAA[J]. Cell, 2013, 154(4): 748-762.
[8] Tanaka Y, Chen ZJ. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway[J]. Sci Signal, 2012, 5(214): ra20.
[9] Zhong B, Zhang L, Lei C, et al. The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA[J]. Immunity, 2009, 30(3): 397-407.
[10] Bhat N, Fitzgerald KA. Recognition of cytosolic DNA by cGAS and other STING-dependent sensors: Highlights[J]. Eur J Immunol, 2014, 44(3): 634-640.
[11] Tsuchida T, Zou J, Saitoh T, et al. The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA[J]. Immunity, 2010, 33(5): 765-776.
[12] Cui H, Liu Y, Huang Y. Roles of TRIM32 in corneal epithelial cells after infection with herpes simplex virus[J]. Int J Exp Cell Physiol Biochem Pharmacol, 2017, 43(2): 801-811.
[13] Sun L, Wu J, Du F, et al. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type Ⅰ interferon pathway[J]. Science, 2013, 339(6121): 786-791.
[14] Zhang X, Shi H, Wu J, et al. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING[J]. Mol Cell, 2013, 51(2): 226-235.
[15] Qiu H, Fan Y, Joyee AG, et al. Type Ⅰ IFNs enhance susceptibility to chlamydia muridarum lung infection by enhancing apoptosis of local macrophages[J]. J Immunol, 2008, 181(3): 2092-2102.
[16] Barker JR, Koestler BJ, Carpenter VK, et al. STING-dependent recognition of cyclic di-AMP mediates type Ⅰ interferon responses during chlamydia trachomatis infection[J]. MBio, 2013, 4(3): e00018-13.
[17] Kim S, Li L, Maliga Z, et al. Anticancer flavonoids are mouse-selective STING agonists[J]. ACS Chem Biol, 2013, 8(7): 1396-1401.
[18] Zhang H, Han MJ, Tao J, et al. Rat and human STINGs profile similarly towards anticancer/antiviral compounds[J]. Sci Rep, 2015, 5: 18035.
[19] Corrales L, Glickman LH, Mcwhirter SM, et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity[J]. Cell Rep, 2015, 11(7): 1018-1030.
[20] Fu J, Kanne DB, Leong M, et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade[J]. Sci Transl Med, 2015, 7(283): 283ra52.
[21] Baird JR, Friedman D, Cottam B, et al. Radiotherapy combined with novel STING-targeting oligonucleotides results in regression of established tumors[J]. Cancer Res, 2016, 76(1): 50-61.
[22] Watson RO, Manzanillo PS, Cox JS. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway[J]. Cell, 2012, 150(4): 803-815.
[23] Watson RO, Bell SL, Macduff DA, et al. The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type Ⅰ interferons and activate autophagy[J]. Cell Host Microbe, 2015, 17(6): 811-819.
[24] Moretti J, Roy S, Bozec D, et al. STING senses microbial viability to orchestrate stress-mediated autophagy of the endoplasmic reticulum[J]. Cell, 2017, 171(4): 809-823.e13.
[25] Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type Ⅰ interferon-dependent innate immunity[J]. Nature, 2009, 461(7265): 788-792.
[26] Lio CW, McDonald B, Takahashi M, et al. cGAS-STING signaling regulates initial innate control of cytomegalovirus infection[J]. J Virol, 2016, 90(17): 7789-7797.
[27] Ma Z, Damania B. The cGAS-STING defense pathway and its counteraction by viruses[J]. Cell Host Microbe, 2016, 19(2): 150-158.
[28] Schoggins JW, Macduff DA, Imanaka N, et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity[J]. Nature, 2014, 505(7485): 691-695.
[29] Li XD, Wu J, Gao D, et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects[J]. Science, 2013, 341(6152): 1390-1394.
[30] Ma Z, Jacobs SR, West JA, et al. Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses[J]. Proc Natl Acad Sci U S A, 2015, 112(31): E4306-E4315.
[31] Paijo J, Doring M, Spanier J, et al. cGAS senses human cytomegalovirus and induces type Ⅰ interferon responses in human monocyte-derived cells[J].PLoS Pathog, 2016, 12(4): e1005546.
[32] Anghelina D, Lam E, Falck-Pederson E. Diminished innate antiviral response to adenovirus vectors in cGAS/STING-deficient mice minimally impacts adaptive immunity[J]. J Virol, 2016, 90(13): 5915-5927.
[33] Reinert LS, Lopusna K, Winther H, et al. Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS[J]. Nat Commun, 2016, 7: 13348.
[34] Holm CK, Rahbek SH, Gad HH, et al. Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses[J]. Nat Commun, 2016, 7: 10680.
[35] Zevini A, Olagnier D, Hiscott J. Crosstalk between cytoplasmic RIG-Ⅰ and STING sensing pathways[J]. Trends Immunol, 2017, 38(3): 194-205.
[36] Barber GN. STING: Infection, inflammation and cancer[J]. Nat Rev Immunol, 2015, 15(12): 760-770.
[37] Aguirre S, Maestre AM, Pagni S, et al. DENV inhibits type Ⅰ IFN production in infected cells by cleaving human STING[J]. PLoS Pathog, 2012, 8(10): e1002934.
[38] Ding Q, Cao X, Lu J, et al. Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity[J]. J Hepatol, 2013, 59(1): 52-58.
[39] Nitta S, Sakamoto N, Nakagawa M, et al. Hepatitis C virus NS4B protein targets STING and abrogates RIG-Ⅰ-mediated type Ⅰ interferon-dependent innate immunity[J]. Hepatology, 2013, 57(1): 46-58.
[40] Li Y, Li C, Xue P, et al. ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response[J]. Proc Natl Acad Sci, 2009, 106(19): 7945-7950.
[41] Abbas YM, Laudenbach BT, Martinez-Montero S, et al. Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2'-O methylations[J]. Proc Natl Acad Sci U S A, 2017, 114(11): E2106-E2115.
[42] Kumar P, Sweeney TR, Skabkin MA, et al. Inhibition of translation by IFIT family members is determined by their ability to interact selectively with the 5'-terminal regions of cap0-, cap1- and 5'ppp-mRNAs[J]. Nucleic Acids Res, 2014, 42(5): 3228-3245.
[43] Xing Y, Chen J, Tu J, et al. The papain-like protease of porcine epidemic diarrhea virus negatively regulates type Ⅰ interferon pathway by acting as a viral deubiquitinase[J]. J Gen Virol, 2013, 94(Pt7): 1554-1567.
[44] Clementz MA, Chen Z, Banach BS, et al. Deubiquitinating and interferon antagonism activities of coronavirus papain-like proteases[J]. J Virol, 2010, 84(9): 4619-4629.
[45] Christensen MH, Jensen SB, Miettinen JJ, et al. HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type Ⅰ IFN expression[J]. EMBO J, 2016, 35(13): 1385-1399.
[46] 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.
[47] He J, Hao R, Liu D, et al. Inhibition of hepatitis B virus replication by activation of the cGAS-STING pathway[J]. J Gen Virol, 2016, 97(12): 3368-3378.