LGP2参与抗病毒天然免疫应答的研究进展
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摘要
RIG-I样受体(RIG-I like receptors,RLRs)是天然免疫系统中一类重要模式识别受体,在细胞天然免疫应答中发挥重要的作用,LGP2是RLRs家族成员之一,对RLRs信号转导有正向和负向调控的双重作用。LGP2依据感染病毒种类的不同发挥着不同的调控作用,但详细作用机制不明确。随着研究的深入,LGP2在天然免疫应答中的作用愈发重要。本文就近年来对LGP2参与RLRs介导的抗病毒天然免疫应答的调控及在不同病毒感染宿主中所起的作用作一综述,以期为LGP2深入研究提供参考。
Retinoic acid-inducible gene-I(RIG-I)-like receptors(RLRs)are important pattern recognition receptors in the innate immune system. LGP2 is a member of the RLRs family,and regulates the signal transduction of RLRs positively and negatively. LGP2 regulation differs according to the virus species in the host. However,the exact mechanisms of action is unknown. Studies have indicated that LGP2 has an important role in antiviral innate immunity. Research progress in LGP2-regulated RLRs that mediate antiviral innate immunity and the roles of LGP2 against infections by different viruses are summarized.
Retinoic acid-inducible gene-I(RIG-I)-like receptors(RLRs)are important pattern recognition receptors in the innate immune system. LGP2 is a member of the RLRs family,and regulates the signal transduction of RLRs positively and negatively. LGP2 regulation differs according to the virus species in the host. However,the exact mechanisms of action is unknown. Studies have indicated that LGP2 has an important role in antiviral innate immunity. Research progress in LGP2-regulated RLRs that mediate antiviral innate immunity and the roles of LGP2 against infections by different viruses are summarized.
引文
[1]王国庆,朱紫祥,曹伟军,刘磊,郑海学. RNA病毒阻断RIG-I样受体识别dsRNA机制研究进展[J].病毒学报,2014,30(6):704-712. DOI:10.13242/j.cnki.bing-duxuebao.002586
[2]曹丽艳,李广兴,王克雄,任玉东,任晓东.细胞质内模式识别受体及其抗病毒免疫研究[J].生命科学,2014,26(9):891-896.
[3] Zheng N X,Wang Y,Hu D D,Yan L,Jiang Y Y. The role of pattern recognition receptors in the innate recogni-tion of Candida albicans[J]. Virulence,2015,6(4):347-361.
[4]翟景波,吕昌龙. RLR家族中RIG-I和MDA-5的研究进展[J].微生物学免疫学进展,2017,45(1):54-59.
[5] Hiscott J,Lin R,Nakhaei P,Paz S. Master CARD:a priceless link to innate immunity[J]. Trends Mol Med,2006,12(2):53-56.
[6] Cheng H,Jiang Z. The essential adaptors of innate im-mune signaling[J]. Protein Cell,2013,4(1):27-39.
[7]王文文. LGP2蛋白在乌鳢水泡病毒感染斑马鱼ZF4细胞中的作用研究[D].武汉:华中农业大学,2015,2-8.
[8]秦成峰,秦鄂德. RIG-I样受体与RNA病毒识别[J].微生物学报,2008,48(10):1418-1423.
[9]丁云磊,孙英杰,王晓旭,胡跃,费荣梅,丁铲. RIG-I样受体信号通路及其调控研究进展[J].中国动物传染病学报,2014(5):72-79.
[10]Kell A M,Jr M G. RIG-I in RNA virus recognition[J].Virology,2015,479-480:110.
[11]Saito T,Hirai R,Loo Y M,Owen D,Johnson C L,Sinha S C,Akira S,Fujita T,Gale M J. Regulation of innate antiviral defenses through a shared repressor do-main in RIG-I and LGP2[J]. Proc Natl Acad Sci U S A,2007,104(2):582-587.
[12]Bruns A M,Leser G P,Lamb R A,Horvath C M. The innate immune sensor LGP2 activates antiviral signaling by regulating MDA5-RNA interaction and filament as-sembly[J]. Mol Cell,2014,55(5):771-781.
[13]Bruns A M,Horvath C M. LGP2 synergy with MDA5in RLR-mediated RNA recognition and antiviral signaling[J]. Cytokine,2015,74(2):198-206.
[14]Pippig D A,Hellmuth J C,Cui S,Kirchhofer A,Lam-mens K,Lammens A,Schmidt A,Rothenfusser S,Hopfner K P. The regulatory domain of the RIG-I family ATPase LGP2 senses double-stranded RNA[J]. Nucle-ic Acids Res,2009,37(6):2014-2025.
[15]Satoh T,Kato H,Kumagai Y,Yoneyama M,Sato S,Matsushita K,Tsujimura T,Fujita T,Akira S,Takeu-chi O. LGP2 is a positive regulator of RIG-I-and MDA5-mediated antiviral responses[J]. Proc Natl Acad Sci U S A,2010,107(4):1512-1517.
[16]Bruns A M,Pollpeter D,Hadizadeh N,Myong S,Mar-ko J F,Horvath C M. ATP hydrolysis enhances RNA recognition and antiviral signal transduction by the innate immune sensor,laboratory of genetics and physiology 2(LGP2)[J]. J Biol Chem,2013,288(2):938-946.
[17]Parisien J P,Lenoir J J,Mandhana R,Rodriguez K R,Qian K,Bruns A M,Horvath C M. RNA sensor LGP2inhibits TRAF ubiquitin ligase to negatively regulate in-nate immune signaling[J/OL]. Embo Rep, 2018:e45176.
[18]Rao Y,Wan Q,Yang C,Su J. Grass carp laboratory of genetics and physiology 2 serves as a negative regulator in retinoic acid-inducible gene I-and melanoma differenti-ation-associated gene 5-mediated antiviral signaling in resting state and early stage of grass carp reovirus infec-tion[J]. Front Immuno,2017,8(352):1-15.
[19]Komuro A,Horvath C M. RNA-and virus-independent inhibition of antiviral signaling by RNA helicase LGP2[J]. J Virol,2006,80(24):12332-12342.
[20]Vilasco M,Larrea E,Vitour D,Dabo S,Breiman A,Regnault B,Riezu J I,Eid P,Prieto J,Meurs E F. The protein kinase IKK epsilon can inhibit HCV expression independently of IFN and its own expression is downreg-ulated in HCV-infected livers[J]. Hepatology,2006,44(6):1635-1647.
[21]Ag V D V,Maillard P V,Schmidt J M,Schmidt J M,Lee S A,Deddouche G S,Borg A,Kjaer S,Snijders A P,Reis e S C. The RIG-I-like receptor LGP2 inhibits Dicer-dependent processing of long double-stranded RNA and blocks RNA interference in mammalian cells[J/OL]. Embo J,2018,37(4):e97479.
[22]Miyamoto M,Komuro A. PACT is required for MDA5-mediated immunoresponses triggered by Cardiovirus in-fection via interaction with LGP2[J]. Biochem Biophys Res Commun,2017,494(2017):227-233.
[23]黄文林.分子病毒学[M].人民卫生出版社,2006,9-15.
[24]Deddouche S,Goubau D,Rehwinkel J,Chakravarty P,Begum S,Maillard P V,Borg A,Matthews N,Feng Q,Van Kuppeveld F J,Reis e S C. Identification of an LGP2-associated MDA5 agonist in picornavirus-infected cells[J/OL]. Elife,2014,3(3):e01535.
[25]Zhu Z,Li C,Du X,Wang G,Cao W,Yang F,Feng H,Zhang X,Shi Z,Liu H,Tian H,Li D,Zhang K,Liu X,Zheng H. Foot-and-mouth disease virus infection inhibits LGP2 protein expression to exaggerate inflam-matory response and promote viral replication[J/OL].Cell Death Dis,2017,8(4):e2747.
[26]Pulido M R,Sánchez-Aparicio M T,Martínez-Salas E,García-Sastre A,Sobrino F,Sáiz M. Innate immune sensor LGP2 is cleaved by the Leader protease of foot-and-mouth disease virus[J/OL]. PLoS Pathog,2018,14(6):e1007135.
[27]Childs K S,Randall R E,Goodbourn S. LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA[J/OL]. PLoS One, 2013, 8(5):e64202.
[28]Kenny R,Rodriguez K R,Horvath C M. Paramyxovi-rus V protein interaction with the antiviral sensor LGP2disrupts MDA5 signaling enhancement but is not rele-vant to LGP2-mediated RLR signaling inhibition[J]. J Virol,2014,88(14):8180-8188.
[29]Childs K,Randall R,Goodbourn S. Paramyxovirus V proteins interact with the RNA Helicase LGP2 to inhibit RIG-I-dependent interferon induction[J]. J Virol,2012,86(7):3411-3421.
[30]Malur M,Jr G M,Krug R M. LGP2 downregulates in-terferon production during infection with seasonal human influenza A viruses that activate interferon regulatory fac-tor 3[J]. J Virol,2012,86(19):10733-10738.
[31]Suthar M S,Ramos H J,Brassil M M,Netland J,Chappell CP,Blahnik G,McMillan A,Diamond MS,Clark EA,Bevan MJ,Gale M Jr. The RIG-I-like recep-tor LGP2 controls CD8(+)T cell survival and fitness[J]. Immunity,2012,37(2):235-248.
[32]黑蕾,钟劲. LGP2在HCV感染诱导的干扰素应答中的关键作用[J].临床肝胆病杂志,2017,33(07):1348.
[33]Hei L,Zhong J. Laboratory of genetics and physiology 2(LGP2)plays an essential role in hepatitis C virus infec-tion-induced interferon responses[J]. Hepatology,2017,65(5):1478.
[34]Venkataraman T,Valdes M,Elsby R,Kakuta S,Cace-res G,Saijo S,Iwakura Y,Barber G N. Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses[J]. J Immunol,2007,178(10):6444-6455.
[35]罗霞,邓国成,赵长臣,廖国礼,陈昆慈,杨小静.池塘养殖斑鳢弹状病毒的分离与初步鉴定[J].水生生物学报,2013,37(7):620-625.
[36]Liniger M,Summerfield A,Zimmer G,McCullough K C,Ruggli N. Chicken cells sense influenza A virus infec-tion through MDA5 and CARDIF signaling involving LGP2[J]. J Virol,2012,86(2):705-717.
[37]Pichlmair A,Schulz O,Tan C P,Rehwinkel J,Kato H,Takeuchi O,Akira S,Way M,Schiavo G,Reis e S C. Activation of MDA5 requires higher-order RNA structures generated during virus infection[J]. J Virol.2009,83(20):10761-10769.
[38]Darja P,Akihiko Komuro,Glen N B,Curt M. Im-paired cellular responses to cytosolic DNA or infection with Listeria monocytogenes and vaccinia virus in the ab-sence of the murine LGP2 protein[J/OL]. PLoS One,2011,6(4):e18842.
[39]Widau R C,Parekh A D,Ranck M C,Golden D W,Kumar K A,Sood R F,Pitroda S P,Liao Z K,Huang X N,Darga T E,Xu D,Huang L,Andrade J,Roiz-man B,Weichselbaum R R,Khodareva N N. RIG-I-like receptor LGP2 protects tumor cells from ionizing ra-diation[J/OL]. Proc Natl Acad Sci U S A,2014,111(4):E484-E491.
[2]曹丽艳,李广兴,王克雄,任玉东,任晓东.细胞质内模式识别受体及其抗病毒免疫研究[J].生命科学,2014,26(9):891-896.
[3] Zheng N X,Wang Y,Hu D D,Yan L,Jiang Y Y. The role of pattern recognition receptors in the innate recogni-tion of Candida albicans[J]. Virulence,2015,6(4):347-361.
[4]翟景波,吕昌龙. RLR家族中RIG-I和MDA-5的研究进展[J].微生物学免疫学进展,2017,45(1):54-59.
[5] Hiscott J,Lin R,Nakhaei P,Paz S. Master CARD:a priceless link to innate immunity[J]. Trends Mol Med,2006,12(2):53-56.
[6] Cheng H,Jiang Z. The essential adaptors of innate im-mune signaling[J]. Protein Cell,2013,4(1):27-39.
[7]王文文. LGP2蛋白在乌鳢水泡病毒感染斑马鱼ZF4细胞中的作用研究[D].武汉:华中农业大学,2015,2-8.
[8]秦成峰,秦鄂德. RIG-I样受体与RNA病毒识别[J].微生物学报,2008,48(10):1418-1423.
[9]丁云磊,孙英杰,王晓旭,胡跃,费荣梅,丁铲. RIG-I样受体信号通路及其调控研究进展[J].中国动物传染病学报,2014(5):72-79.
[10]Kell A M,Jr M G. RIG-I in RNA virus recognition[J].Virology,2015,479-480:110.
[11]Saito T,Hirai R,Loo Y M,Owen D,Johnson C L,Sinha S C,Akira S,Fujita T,Gale M J. Regulation of innate antiviral defenses through a shared repressor do-main in RIG-I and LGP2[J]. Proc Natl Acad Sci U S A,2007,104(2):582-587.
[12]Bruns A M,Leser G P,Lamb R A,Horvath C M. The innate immune sensor LGP2 activates antiviral signaling by regulating MDA5-RNA interaction and filament as-sembly[J]. Mol Cell,2014,55(5):771-781.
[13]Bruns A M,Horvath C M. LGP2 synergy with MDA5in RLR-mediated RNA recognition and antiviral signaling[J]. Cytokine,2015,74(2):198-206.
[14]Pippig D A,Hellmuth J C,Cui S,Kirchhofer A,Lam-mens K,Lammens A,Schmidt A,Rothenfusser S,Hopfner K P. The regulatory domain of the RIG-I family ATPase LGP2 senses double-stranded RNA[J]. Nucle-ic Acids Res,2009,37(6):2014-2025.
[15]Satoh T,Kato H,Kumagai Y,Yoneyama M,Sato S,Matsushita K,Tsujimura T,Fujita T,Akira S,Takeu-chi O. LGP2 is a positive regulator of RIG-I-and MDA5-mediated antiviral responses[J]. Proc Natl Acad Sci U S A,2010,107(4):1512-1517.
[16]Bruns A M,Pollpeter D,Hadizadeh N,Myong S,Mar-ko J F,Horvath C M. ATP hydrolysis enhances RNA recognition and antiviral signal transduction by the innate immune sensor,laboratory of genetics and physiology 2(LGP2)[J]. J Biol Chem,2013,288(2):938-946.
[17]Parisien J P,Lenoir J J,Mandhana R,Rodriguez K R,Qian K,Bruns A M,Horvath C M. RNA sensor LGP2inhibits TRAF ubiquitin ligase to negatively regulate in-nate immune signaling[J/OL]. Embo Rep, 2018:e45176.
[18]Rao Y,Wan Q,Yang C,Su J. Grass carp laboratory of genetics and physiology 2 serves as a negative regulator in retinoic acid-inducible gene I-and melanoma differenti-ation-associated gene 5-mediated antiviral signaling in resting state and early stage of grass carp reovirus infec-tion[J]. Front Immuno,2017,8(352):1-15.
[19]Komuro A,Horvath C M. RNA-and virus-independent inhibition of antiviral signaling by RNA helicase LGP2[J]. J Virol,2006,80(24):12332-12342.
[20]Vilasco M,Larrea E,Vitour D,Dabo S,Breiman A,Regnault B,Riezu J I,Eid P,Prieto J,Meurs E F. The protein kinase IKK epsilon can inhibit HCV expression independently of IFN and its own expression is downreg-ulated in HCV-infected livers[J]. Hepatology,2006,44(6):1635-1647.
[21]Ag V D V,Maillard P V,Schmidt J M,Schmidt J M,Lee S A,Deddouche G S,Borg A,Kjaer S,Snijders A P,Reis e S C. The RIG-I-like receptor LGP2 inhibits Dicer-dependent processing of long double-stranded RNA and blocks RNA interference in mammalian cells[J/OL]. Embo J,2018,37(4):e97479.
[22]Miyamoto M,Komuro A. PACT is required for MDA5-mediated immunoresponses triggered by Cardiovirus in-fection via interaction with LGP2[J]. Biochem Biophys Res Commun,2017,494(2017):227-233.
[23]黄文林.分子病毒学[M].人民卫生出版社,2006,9-15.
[24]Deddouche S,Goubau D,Rehwinkel J,Chakravarty P,Begum S,Maillard P V,Borg A,Matthews N,Feng Q,Van Kuppeveld F J,Reis e S C. Identification of an LGP2-associated MDA5 agonist in picornavirus-infected cells[J/OL]. Elife,2014,3(3):e01535.
[25]Zhu Z,Li C,Du X,Wang G,Cao W,Yang F,Feng H,Zhang X,Shi Z,Liu H,Tian H,Li D,Zhang K,Liu X,Zheng H. Foot-and-mouth disease virus infection inhibits LGP2 protein expression to exaggerate inflam-matory response and promote viral replication[J/OL].Cell Death Dis,2017,8(4):e2747.
[26]Pulido M R,Sánchez-Aparicio M T,Martínez-Salas E,García-Sastre A,Sobrino F,Sáiz M. Innate immune sensor LGP2 is cleaved by the Leader protease of foot-and-mouth disease virus[J/OL]. PLoS Pathog,2018,14(6):e1007135.
[27]Childs K S,Randall R E,Goodbourn S. LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA[J/OL]. PLoS One, 2013, 8(5):e64202.
[28]Kenny R,Rodriguez K R,Horvath C M. Paramyxovi-rus V protein interaction with the antiviral sensor LGP2disrupts MDA5 signaling enhancement but is not rele-vant to LGP2-mediated RLR signaling inhibition[J]. J Virol,2014,88(14):8180-8188.
[29]Childs K,Randall R,Goodbourn S. Paramyxovirus V proteins interact with the RNA Helicase LGP2 to inhibit RIG-I-dependent interferon induction[J]. J Virol,2012,86(7):3411-3421.
[30]Malur M,Jr G M,Krug R M. LGP2 downregulates in-terferon production during infection with seasonal human influenza A viruses that activate interferon regulatory fac-tor 3[J]. J Virol,2012,86(19):10733-10738.
[31]Suthar M S,Ramos H J,Brassil M M,Netland J,Chappell CP,Blahnik G,McMillan A,Diamond MS,Clark EA,Bevan MJ,Gale M Jr. The RIG-I-like recep-tor LGP2 controls CD8(+)T cell survival and fitness[J]. Immunity,2012,37(2):235-248.
[32]黑蕾,钟劲. LGP2在HCV感染诱导的干扰素应答中的关键作用[J].临床肝胆病杂志,2017,33(07):1348.
[33]Hei L,Zhong J. Laboratory of genetics and physiology 2(LGP2)plays an essential role in hepatitis C virus infec-tion-induced interferon responses[J]. Hepatology,2017,65(5):1478.
[34]Venkataraman T,Valdes M,Elsby R,Kakuta S,Cace-res G,Saijo S,Iwakura Y,Barber G N. Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses[J]. J Immunol,2007,178(10):6444-6455.
[35]罗霞,邓国成,赵长臣,廖国礼,陈昆慈,杨小静.池塘养殖斑鳢弹状病毒的分离与初步鉴定[J].水生生物学报,2013,37(7):620-625.
[36]Liniger M,Summerfield A,Zimmer G,McCullough K C,Ruggli N. Chicken cells sense influenza A virus infec-tion through MDA5 and CARDIF signaling involving LGP2[J]. J Virol,2012,86(2):705-717.
[37]Pichlmair A,Schulz O,Tan C P,Rehwinkel J,Kato H,Takeuchi O,Akira S,Way M,Schiavo G,Reis e S C. Activation of MDA5 requires higher-order RNA structures generated during virus infection[J]. J Virol.2009,83(20):10761-10769.
[38]Darja P,Akihiko Komuro,Glen N B,Curt M. Im-paired cellular responses to cytosolic DNA or infection with Listeria monocytogenes and vaccinia virus in the ab-sence of the murine LGP2 protein[J/OL]. PLoS One,2011,6(4):e18842.
[39]Widau R C,Parekh A D,Ranck M C,Golden D W,Kumar K A,Sood R F,Pitroda S P,Liao Z K,Huang X N,Darga T E,Xu D,Huang L,Andrade J,Roiz-man B,Weichselbaum R R,Khodareva N N. RIG-I-like receptor LGP2 protects tumor cells from ionizing ra-diation[J/OL]. Proc Natl Acad Sci U S A,2014,111(4):E484-E491.