抗DNA病毒信号通路cGAS-STING的研究进展
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摘要
病毒感染后,宿主的固有免疫系统快速地识别病毒并作出应答反应,但免疫系统识别和清除病毒的机制尚未完全阐明。研究表明,细胞识别和检测病毒主要通过受体完成,而环鸟苷酸-腺苷酸合成酶(cyclic GMPAMP synthase,cGAS)是一种新发现的DNA识别受体,它将信号传递给下游的干扰素刺激基因(stimulator of interferon genes,STING)蛋白,诱导产生I型干扰素(type I interferon,IFN-I),从而启动细胞抗病毒免疫反应。本文综述了cGAS-STING信号通路的作用机制及抗病毒相关研究,以期为抗病毒药物的研发提供理论依据。
Innate immune system rapidly detects and responds to viruses at the early stage of viral infection.However,the mechanisms by which the immune system recognizes and eliminates them have not been fully clarified so far.Studies have shown that receptors are the primary tool for cell recognition and detection of viruses,and cyclic GMP-AMP synthase(cGAS) is one of the newly found DNA recognition receptors. cGAS transmits the signal to the downstream protein called STING(stimulator of interferon genes) and mediates the production of type I interferon(IFN-I),thereby to initiates the antiviral immunity of cells. This review briefly introduces the mechanism of the cGAS-STING signaling pathway,in order to provide a theoretical basis for the research and development of new antiviral drugs.
Innate immune system rapidly detects and responds to viruses at the early stage of viral infection.However,the mechanisms by which the immune system recognizes and eliminates them have not been fully clarified so far.Studies have shown that receptors are the primary tool for cell recognition and detection of viruses,and cyclic GMP-AMP synthase(cGAS) is one of the newly found DNA recognition receptors. cGAS transmits the signal to the downstream protein called STING(stimulator of interferon genes) and mediates the production of type I interferon(IFN-I),thereby to initiates the antiviral immunity of cells. This review briefly introduces the mechanism of the cGAS-STING signaling pathway,in order to provide a theoretical basis for the research and development of new antiviral drugs.
引文
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[2]Stein SC,Lam E,Falck-Pedersen E.Cell-specific regulation of nucleic acid sensor cascades:a controlling interest in the antiviral response[J].J Virol,2012,86(24):13303-13312.
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[4]Luo WW,Li S,Li C,et al.iRhom2 is essential for innate immunity to DNA viruses by mediating trafficking and stability of the adaptor STING[J].Nat Immunol,2016,17(9):1057-1066.
[5]Gao D,Wu J,Wu YT,et al.Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses[J].Science,2013,341(6148):903-906.
[6]Hu MM,Yang Q,Xie XQ,et al.Sumoylation promotes the stability of the DNA sensor c GAS and the adaptor STING to regulate the kinetics of response to DNA virus[J].Immunity,2016,45(3):555-569.
[7]Jin L,Hill KK,Filak H,et al.MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di-AMP and cyclic-di-GMP[J].J Immunol,2011,187(5):2595-2601.
[8]丁亮,泥艳红,胡勤刚,等.新型胞质DNA感受通路:c GAS-STING的研究进展[J].生物化学与生物物理进展,2014,41(9):830-838.
[9]Lio CW,Mc Donald B,Takahashi M,et al.c GAS-STING signaling regulates initial innate control of cytomegalovirus infection[J].J Virol,2016,90(17):7789-7797.
[10]Li X,Shu C,Yi G,et al.Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization[J].Immunity,2013,39(6):1019-1031.
[11]谢欣,王孝伟,刘俊义.免疫途径抗HIV信号通路:c GASSTING研究进展[J].国际药学研究杂志,2014,41(5):528-532.
[12]原慧,陶佳丽,张亮,等.c GAS——一种胞质DNA感应器的研究进展[J].免疫学杂志,2016,32(11):997-1000.
[13]Xiao TS,Fitzgerald KA.The c GAS-STING pathway for DNA sensing[J].Mol Cell,2013,51(2):135-139.
[14]Shu C,Li X,Li P.The mechanism of double-stranded DNA sensing through the c GAS-STING pathway[J].Cytokine Growth Factor Rev,2014,25(6):641-648.
[15]Chen Q,Sun L,Chen ZJ.Regulation and function of the c GASSTING pathway of cytosolic DNA sensing[J].Nat Immunol,2016,17(10):1142-1149.
[16]郑洋,邢雅玲,陈晓娟,等.STING在宿主天然免疫信号通路中的调节作用[J].生物化学与生物物理进展,2013,10(1):5-14.
[17]Burdette DL,Vance RE.STING and the innate immune response to nucleic acids in the cytosol[J].Nat Immunol,2013,14(1):19-26.
[18]Konno H,Barber GN.The STING controlled cytosolic-DNA activated innate immune pathway and microbial disease[J].Microbes Infect,2014,16(12):998-1001.
[19]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.
[20]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.
[21]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.
[22]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.
[23]Ishikawa H,Barber GN.STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling[J].Nature,2008,455(7213):674-678.
[24]Barber GN.Cytoplasmic DNA innate immune pathways[J].Immunol Rev,2011,243(1):99-108.
[25]Paludan SR,Bowie AG.Immune sensing of DNA[J].Immunity,2013,38(5):870-880.
[26]Abe T,Harashima A,Xia T,et al.STING recognition of cytoplasmic DNA instigates cellular defense[J].Mol Cell,2013,50(1):5-15.
[27]Cavlar T,Ablasser A,Hornung V.Induction of type I IFNs by intracellular DNA-sensing pathways[J].Immunol Cell Biol,2012,90(5):474-482.
[28]Anghelina D,Lam E,Falck-Pedersen E.Diminished innate antiviral response to adenovirus vectors in c GAS/STING-deficient mice minimally impacts adaptive immunity[J].J Virol,2016,90(13):5915-5927.
[29]Ma Z,Jacobs SR,West JA,et al.Modulation of the c GASSTING DNA sensing pathway by gammaherpesviruses[J].Proc Natl Acad Sci U S A,2015,112(31):E4306-E4315.
[30]Chen X,Yang X,Zheng Y,et al.SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex[J].Protein Cell,2014,5(5):369-381.
[31]Christensen MH,Paludan SR.Viral evasion of DNA-stimulated innate immune responses[J].Cell Mol Immunol,2017,14(1):4-13.
[32]Chan YK,Gack MU.Viral evasion of intracellular DNA and RNA sensing[J].Nat Rev Microbiol,2016,14(6):360-373.
[2]Stein SC,Lam E,Falck-Pedersen E.Cell-specific regulation of nucleic acid sensor cascades:a controlling interest in the antiviral response[J].J Virol,2012,86(24):13303-13312.
[3]Zhou Q,Lin H,Wang S,et al.The ER-associated protein ZDHHC1 is a positive regulator of DNA virus-triggered,MITA/STING-dependent innate immune signaling[J].Cell Host Microbe,2014,16(4):450-461.
[4]Luo WW,Li S,Li C,et al.iRhom2 is essential for innate immunity to DNA viruses by mediating trafficking and stability of the adaptor STING[J].Nat Immunol,2016,17(9):1057-1066.
[5]Gao D,Wu J,Wu YT,et al.Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses[J].Science,2013,341(6148):903-906.
[6]Hu MM,Yang Q,Xie XQ,et al.Sumoylation promotes the stability of the DNA sensor c GAS and the adaptor STING to regulate the kinetics of response to DNA virus[J].Immunity,2016,45(3):555-569.
[7]Jin L,Hill KK,Filak H,et al.MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di-AMP and cyclic-di-GMP[J].J Immunol,2011,187(5):2595-2601.
[8]丁亮,泥艳红,胡勤刚,等.新型胞质DNA感受通路:c GAS-STING的研究进展[J].生物化学与生物物理进展,2014,41(9):830-838.
[9]Lio CW,Mc Donald B,Takahashi M,et al.c GAS-STING signaling regulates initial innate control of cytomegalovirus infection[J].J Virol,2016,90(17):7789-7797.
[10]Li X,Shu C,Yi G,et al.Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization[J].Immunity,2013,39(6):1019-1031.
[11]谢欣,王孝伟,刘俊义.免疫途径抗HIV信号通路:c GASSTING研究进展[J].国际药学研究杂志,2014,41(5):528-532.
[12]原慧,陶佳丽,张亮,等.c GAS——一种胞质DNA感应器的研究进展[J].免疫学杂志,2016,32(11):997-1000.
[13]Xiao TS,Fitzgerald KA.The c GAS-STING pathway for DNA sensing[J].Mol Cell,2013,51(2):135-139.
[14]Shu C,Li X,Li P.The mechanism of double-stranded DNA sensing through the c GAS-STING pathway[J].Cytokine Growth Factor Rev,2014,25(6):641-648.
[15]Chen Q,Sun L,Chen ZJ.Regulation and function of the c GASSTING pathway of cytosolic DNA sensing[J].Nat Immunol,2016,17(10):1142-1149.
[16]郑洋,邢雅玲,陈晓娟,等.STING在宿主天然免疫信号通路中的调节作用[J].生物化学与生物物理进展,2013,10(1):5-14.
[17]Burdette DL,Vance RE.STING and the innate immune response to nucleic acids in the cytosol[J].Nat Immunol,2013,14(1):19-26.
[18]Konno H,Barber GN.The STING controlled cytosolic-DNA activated innate immune pathway and microbial disease[J].Microbes Infect,2014,16(12):998-1001.
[19]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.
[20]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.
[21]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.
[22]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.
[23]Ishikawa H,Barber GN.STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling[J].Nature,2008,455(7213):674-678.
[24]Barber GN.Cytoplasmic DNA innate immune pathways[J].Immunol Rev,2011,243(1):99-108.
[25]Paludan SR,Bowie AG.Immune sensing of DNA[J].Immunity,2013,38(5):870-880.
[26]Abe T,Harashima A,Xia T,et al.STING recognition of cytoplasmic DNA instigates cellular defense[J].Mol Cell,2013,50(1):5-15.
[27]Cavlar T,Ablasser A,Hornung V.Induction of type I IFNs by intracellular DNA-sensing pathways[J].Immunol Cell Biol,2012,90(5):474-482.
[28]Anghelina D,Lam E,Falck-Pedersen E.Diminished innate antiviral response to adenovirus vectors in c GAS/STING-deficient mice minimally impacts adaptive immunity[J].J Virol,2016,90(13):5915-5927.
[29]Ma Z,Jacobs SR,West JA,et al.Modulation of the c GASSTING DNA sensing pathway by gammaherpesviruses[J].Proc Natl Acad Sci U S A,2015,112(31):E4306-E4315.
[30]Chen X,Yang X,Zheng Y,et al.SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex[J].Protein Cell,2014,5(5):369-381.
[31]Christensen MH,Paludan SR.Viral evasion of DNA-stimulated innate immune responses[J].Cell Mol Immunol,2017,14(1):4-13.
[32]Chan YK,Gack MU.Viral evasion of intracellular DNA and RNA sensing[J].Nat Rev Microbiol,2016,14(6):360-373.