免疫途径抗HIV信号通路:cGAS-STING研究进展
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摘要
干扰素基因刺激蛋白(stimulator of interferon genes,STING)是天然免疫信号通路中重要接头蛋白,环鸟苷酸-腺苷酸合成酶(cyclic GMP-AMP synthase,cGAS)是其上游DNA识别受体,两者共同参与的cGAS-STING通路在识别外源性DNA、介导产生Ⅰ型干扰素的过程中发挥重要。最近研究结果表明,人类免疫缺陷病毒(human immunodeficiency virus,HIV)入侵宿主细胞后,能激活cGAS-STING通路,诱导天然免疫反应,抑制HIV病毒活性。本文将对该信号通路的作用机制及相关内容加以综述,以期为开拓新的抗HIV药物靶点和分子设计提供新思路。
Stimulator of interferon genes(STING)are important adaptor proteins in innate immune-related signal pathway. The upstream protein,cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS),is cytosolic DNA sensor. Detection of cytosolic DNA,cGAS-STING pathway can be activated and subsequently activate the type Ⅰ interferon(IFN) antiviral response.Recent studies indicated that retroviruses especially HIV can activate the host innate immune system through cGAS-STING pathway and trigger robust immune response. In this review,we briefly describe the mechanism of innate immune activated by the newly discovered cGAS-STING pathway and highlight recent progress in STING agonist.
Stimulator of interferon genes(STING)are important adaptor proteins in innate immune-related signal pathway. The upstream protein,cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS),is cytosolic DNA sensor. Detection of cytosolic DNA,cGAS-STING pathway can be activated and subsequently activate the type Ⅰ interferon(IFN) antiviral response.Recent studies indicated that retroviruses especially HIV can activate the host innate immune system through cGAS-STING pathway and trigger robust immune response. In this review,we briefly describe the mechanism of innate immune activated by the newly discovered cGAS-STING pathway and highlight recent progress in STING agonist.
引文
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[3]Wu J,Sun L,Chen X,et al.Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA[J].Science,2013,339(6121):826-830.
[4]Sun L,Wu J,Du F,et al.Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the typeⅠinterferon pathway[J].Science,2013,339(6121):786-791.
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[6]Cavlar T,Deimling T,Ablasser A,et al.Species-specific detection of the antiviral small-molecule compound CMA by STING[J].EMBO J,2013,32(10):1440-1450.
[7]KranzuschPJ,LeeAS,BergerJM,et al.StructureofhumancGAS reveals a conserved family of second-messenger enzymes in innate immunity[J].Cell Rep,2013,3(5):1362-1368.
[8]CivrilF,DelmilingT,DeOliveiraMannCC,et al.Structuralmechanism of cytosolic DNA sensing by cGAS[J].Nature,2013,498(7454):332-337.
[9]Ablasser A,Goldeck M,Cavlar T,et al.cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING[J].Nature,2013,498(7454):380-384.
[10]Panne D.Immunology:cytosolic DNA sensing unraveled[J].Nat Chem Biol,2013,9(9):533-534.
[11]Xiao TS,Fitzgerald KA.The cGAS-STING pathway for DNA sensing[J].Mol Cell,2013,51(2):135-139.
[12]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.
[13]Ishikawa H,Barber GN.STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling[J].Nature,2008,455(7213):674-678.
[14]Jin L,Waterman PM,Jonscher KR,et al.MPYS,a novel membrane tetraspanner,is associated with major histocompatibility complex classⅡand mediates transduction of apoptotic signals[J].Mol Cell Biol.2008,28(16):5014-5026.
[15]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.
[16]Huang YH,Liu XY,Du XX,et al.The structural basis for the sensing and binding of cyclic di-GMP by STING[J].Nat Struct Mol Biol,2012,19(7):728-730.
[17]Parvatiyar K,Zhang Z,Teles RM,et al.The helicase DDX41recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate typeⅠinterferon immune response[J].Nat Immunol,2012,13(12):1155-1161.
[18]ShangG,Zhu D,Lin Y,et al.Crystal structures of STING protein reveal basis for recognition of cyclic di-GMP[J].Nat Struct Mol Biol,2012,19(7):725-727.
[19]DinerEJ,BurdetteDL,WilsonSC,et al.TheinnateimmuneDNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING[J].Cell Rep,2013,3(5):1355-1361.
[20]OuyangSX,WangY,RuH,et al.StructuralanalysisoftheSTING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding[J].Immunity,2012,36(6):1073-1086.
[21]Shu C,Yi G,Watts T,et al.Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system[J].Nat Struct Mol Biol,2012,19(7):722-724.
[22]DinerEJ,BurdetteDL,WilsonSC,et al.TheinnateimmuneDNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING[J].Cell Rep,2013,3(5):1355-1361.
[23]Keatine SE,Baran M,Bowlea G.Cytosolic DNA sensors regulating typeⅠinterferon induction[J].Trends Immunol,2011,32(12):574-581.
[24]Paludan SR,Bowle AG.Immune sensing of DNA[J].Immunity,2013,38(5):870-880.
[25]Kim S,Li L,Maliqa Z,et al.Anticancer flavonoids are mouseselective STING agonists[J].ACS Chem Biol,2013,8(7):1396-1401.
[26]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.
[27]Barker JR,Koestler BJ,Carpenter VK,et al.STING-dependent recognition of cyclic di-AMP mediates typeⅠinterferon responses during Chlamydia trachomatis infection[J].MBio,2013,4(3):e00018-e00013.
[2]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.
[3]Wu J,Sun L,Chen X,et al.Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA[J].Science,2013,339(6121):826-830.
[4]Sun L,Wu J,Du F,et al.Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the typeⅠinterferon pathway[J].Science,2013,339(6121):786-791.
[5]Gao P,Ascano M,Wu Y,et al.Cyclic[G(2',5')pA(3',5')p]is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase[J].Cell,2013,153(5):1094-1107.
[6]Cavlar T,Deimling T,Ablasser A,et al.Species-specific detection of the antiviral small-molecule compound CMA by STING[J].EMBO J,2013,32(10):1440-1450.
[7]KranzuschPJ,LeeAS,BergerJM,et al.StructureofhumancGAS reveals a conserved family of second-messenger enzymes in innate immunity[J].Cell Rep,2013,3(5):1362-1368.
[8]CivrilF,DelmilingT,DeOliveiraMannCC,et al.Structuralmechanism of cytosolic DNA sensing by cGAS[J].Nature,2013,498(7454):332-337.
[9]Ablasser A,Goldeck M,Cavlar T,et al.cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING[J].Nature,2013,498(7454):380-384.
[10]Panne D.Immunology:cytosolic DNA sensing unraveled[J].Nat Chem Biol,2013,9(9):533-534.
[11]Xiao TS,Fitzgerald KA.The cGAS-STING pathway for DNA sensing[J].Mol Cell,2013,51(2):135-139.
[12]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.
[13]Ishikawa H,Barber GN.STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling[J].Nature,2008,455(7213):674-678.
[14]Jin L,Waterman PM,Jonscher KR,et al.MPYS,a novel membrane tetraspanner,is associated with major histocompatibility complex classⅡand mediates transduction of apoptotic signals[J].Mol Cell Biol.2008,28(16):5014-5026.
[15]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.
[16]Huang YH,Liu XY,Du XX,et al.The structural basis for the sensing and binding of cyclic di-GMP by STING[J].Nat Struct Mol Biol,2012,19(7):728-730.
[17]Parvatiyar K,Zhang Z,Teles RM,et al.The helicase DDX41recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate typeⅠinterferon immune response[J].Nat Immunol,2012,13(12):1155-1161.
[18]ShangG,Zhu D,Lin Y,et al.Crystal structures of STING protein reveal basis for recognition of cyclic di-GMP[J].Nat Struct Mol Biol,2012,19(7):725-727.
[19]DinerEJ,BurdetteDL,WilsonSC,et al.TheinnateimmuneDNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING[J].Cell Rep,2013,3(5):1355-1361.
[20]OuyangSX,WangY,RuH,et al.StructuralanalysisoftheSTING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding[J].Immunity,2012,36(6):1073-1086.
[21]Shu C,Yi G,Watts T,et al.Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system[J].Nat Struct Mol Biol,2012,19(7):722-724.
[22]DinerEJ,BurdetteDL,WilsonSC,et al.TheinnateimmuneDNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING[J].Cell Rep,2013,3(5):1355-1361.
[23]Keatine SE,Baran M,Bowlea G.Cytosolic DNA sensors regulating typeⅠinterferon induction[J].Trends Immunol,2011,32(12):574-581.
[24]Paludan SR,Bowle AG.Immune sensing of DNA[J].Immunity,2013,38(5):870-880.
[25]Kim S,Li L,Maliqa Z,et al.Anticancer flavonoids are mouseselective STING agonists[J].ACS Chem Biol,2013,8(7):1396-1401.
[26]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.
[27]Barker JR,Koestler BJ,Carpenter VK,et al.STING-dependent recognition of cyclic di-AMP mediates typeⅠinterferon responses during Chlamydia trachomatis infection[J].MBio,2013,4(3):e00018-e00013.