线粒体调控先天性免疫机制研究进展
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摘要
线粒体是真核细胞中参与细胞代谢和细胞程序性死亡的重要的细胞器。除此之外,线粒体还与宿主细胞抗病毒先天性免疫有密切的关系。线粒体首次被证实参与先天性免疫调控是基于线粒体抗病毒信号蛋白(mitochondrial antiviral-signaling protein,MAVS)的发现,MAVS锚定于线粒体,是RIG-I样受体信号传导中的关键接头蛋白。最近,其他先天免疫分子,如NLRX1、TRAF6、NLRP3和IRGM等也被证实与线粒体相关,说明线粒体能够作为先天性免疫的平台发挥抗病毒作用。此外,损伤线粒体可释放一系列损伤相关分子模式,其中线粒体DNA(mt DNA)的释放能够激活TLR9、NLRP3和STING等一系列先天性免疫信号通路。本文简单介绍了线粒体的功能,总结了线粒体如何调控抗病毒先天性免疫,以期为细胞器水平进行病毒防控提供新策略。
The mitochondrion is an important organelle in eukaryotic cells,which is involved in cell metabolism and programmed cell death. In addition, mitochondrion is closely related to host antiviral innate immunity. The cloning and function analysis of mitochondrial antiviral signal protein(MAVS) for the ?rst time have demonstrated the involvement of mitochondrion in innate immunity. MAVS is anchored to mitochondria and plays as a key adaptor protein in RIG-I-like receptor signaling. Recently, other innate immune molecules,such as NLRX1, TRAF6, NLRP3 and IRGM have also been shown to be associated with mitochondria, indicating that mitochondria can act as a platform for antiviral innate immunity. In addition, damaged mitochondria can release a series of damage-related molecular patterns(DAMPs), in which the release of mitochondrial DNA(mtDNA) can activate a series of innate immune signaling pathways such as TLR9, NLRP3 and STING. This review brie?y introduces the functions of mitochondria, summarizes how mitochondrion regulates antiviral innate immunity, and provides new strategies for virus prevention and control at organelles level.
The mitochondrion is an important organelle in eukaryotic cells,which is involved in cell metabolism and programmed cell death. In addition, mitochondrion is closely related to host antiviral innate immunity. The cloning and function analysis of mitochondrial antiviral signal protein(MAVS) for the ?rst time have demonstrated the involvement of mitochondrion in innate immunity. MAVS is anchored to mitochondria and plays as a key adaptor protein in RIG-I-like receptor signaling. Recently, other innate immune molecules,such as NLRX1, TRAF6, NLRP3 and IRGM have also been shown to be associated with mitochondria, indicating that mitochondria can act as a platform for antiviral innate immunity. In addition, damaged mitochondria can release a series of damage-related molecular patterns(DAMPs), in which the release of mitochondrial DNA(mtDNA) can activate a series of innate immune signaling pathways such as TLR9, NLRP3 and STING. This review brie?y introduces the functions of mitochondria, summarizes how mitochondrion regulates antiviral innate immunity, and provides new strategies for virus prevention and control at organelles level.
引文
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[32]Singh S B,Davis A S,Taylor G A,et al.Human IRGM induces autophagy to eliminate intracellular mycobacteria[J].Science,2006,313(5792):1438-1441.
[33]Singh S B,Ornatowski W,Vergne I,et al.Human IRGMregulates autophagy and cell-autonomous immunity functions through mitochondria[J].Nat Cell Biol,2010,12(12):1154-1165.
[34]Garrido C,Galluzzi L,Brunet M,et al.Mechanisms of cytochrome c release from mitochondria[J].Cell Death Differ,2006,13(9):1423-1433.
[35]Wei X,Shao B,He Z,et al.Cationic nanocarriers induce cell necrosis through impairment of Na(+)/K(+)-ATPase and cause subsequent inflammatory response[J].Cell Res,2015,25(2):237-253.
[36]Gurung P,Lukens J R,Kanneganti T D.Mitochondria:diversity in the regulation of the NLRP3 inflammasome[J].Trends Mol Med,2015,21(3):193-201.
[37]White M J,Mcarthur K,Metcalf D,et al.Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production[J].Cell,2014,159(7):1549-1562.
[38]Zhang J Z,Liu Z,Liu J,et al.Mitochondrial DNA induces inflammation and increases TLR9/NF-κB expression in lung tissue[J].Int J Mol Med,2014,33(4):817-824.
[39]Rongvaux A,Jackson R,Harman C C,et al.Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA[J].Cell,2014,159(7):1563-1577.
[40]Sun B,Sundstr?m K,Chew J J,et al.Dengue virus activates cGAS through the release of mitochondrial DNA[J].Sci Rep,2017,7(1):3594.
[41]Aguirre S,Luthra P,Sanchez-Aparicio M T,et al.Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection[J].Nat Microbiol,2017,2:17037.
[42]Nakahira K,Haspel J A,Rathinam V A,et al.Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome[J].Nat Immunol,2011,12(3):222-230.
[2]Schwarzl?nder M,Logan D C,Johnston I G,et al.Pulsing of membrane potential in individual mitochondria:a stress-induced mechanism to regulate respiratory bioenergetics in Arabidopsis[J].Plant Cell,2012,24(3):1188-1201.
[3]Kawai T,Takahashi K,Sato S,et al.IPS-1,an adaptor triggering RIG-I-and Mda5-mediated type I interferon induction[J].Nat Immunol,2005,6(10):981-988.
[4]Meylan E,Curran J,Hofmann K,et al.Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus[J].Nature,2005,437(7062):1167-1172.
[5]Seth R B,Sun L,Ea C K,et al.Identification and characterization of MAVS,a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3[J].Cell,2005,122(5):669-682.
[6]Xu L G,Wang Y Y,Han K J,et al.VISA is an adapter protein required for virus-triggered IFN-beta signaling[J].Mol Cell,2005,19(6):727-740.
[7]Akira S,Takeda K.Toll-like receptor signalling[J].Nat Rev Immunol,2004,4(7):499-511.
[8]Takeuchi O,Akira S.Pattern recognition receptors and inflammation[J].Cell,2010,140(6):805-820.
[9]Yoneyama M,Kikuchi M,Natsukawa T,et al.The RNAhelicase RIG-I has an essential function in doublestranded RNA-induced innate antiviral responses[J].Nat Immunol,2004,5(7):730-737.
[10]Yoneyama M,Fujita T.Structural mechanism of RNArecognition by the RIG-I-like receptors[J].Immunity,2008,29(2):178-181.
[11]Kumar H,Kawai T,Kato H,et al.Essential role of IPS-1 in innate immune responses against RNA viruses[J].JExp Med,2006,203(7):1795-1803.
[12]Sun Q,Sun L,Liu H H,et al.The specific and essential role of MAVS in antiviral innate immune responses[J].Immunity,2006,24(5):633-642.
[13]Chan D C.Mitochondria:dynamic organelles in disease,aging,and development[J].Cell,2006,125(7):1241-1252.
[14]Castanier C,Garcin D,Vazquez A,et al.Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway[J].EMBO Rep,2010,11(2):133-138.
[15]Onoguchi K,Onomoto K,Takamatsu S,et al.Virusinfection or 5'ppp-RNA activates antiviral signal through redistribution of IPS-1 mediated by MFN1[J].PLoSPathog,2010,6(7):e1001012.
[16]Ishikawa H,Barber G N.STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling[J].Nature,2008,455(7213):674-678.
[17]Yasukawa K,Oshiumi H,Takeda M,et al.Mitofusin 2inhibits mitochondrial antiviral signaling[J].Sci Signal,2009,2(84):ra47.
[18]Moore C B,Bergstralh D T,Duncan J A,et al.NLRX1is a regulator of mitochondrial antiviral immunity[J].Nature,2008,451(7178):573-577.
[19]Xu L,Xiao N,Liu F,et al.Inhibition of RIG-I and MDA5-dependent antiviral response by gC1qR at mitochondria[J].Proc Natl Acad Sci USA,2009,106(5):1530-1535.
[20]Koshiba T,Yasukawa K,Yanagi Y,et al.Mitochondrial membrane potential is required for MAVS-mediated antiviral signaling[J].Sci Signal,2011,4(158):ra7.
[21]Naik E,Dixit V M.Mitochondrial reactive oxygen species drive proinflammatory cytokine production[J].J Exp Med,2011,208(3):417-420.
[22]Soucy-Faulkner A,Mukawera E,Fink K,et al.Requirement of NOX2 and reactive oxygen species for efficient RIG-I-mediated antiviral response through regulation of MAVS expression[J].PLoS Pathog,2010,6(6):e1000930.
[23]Benko S,Philpott D J,Girardin S E.The microbial and danger signals that activate Nod-like receptors[J].Cytokine,2008,43(3):368-373.
[24]Tschopp J,Schroder K.NLRP3 inflammasome activation:the convergence of multiple signalling pathways on ROSproduction?[J].Nat Rev Immunol,2010,10(3):210-215.
[25]Van Bruggen R,K?ker M Y,Jansen M,et al.Human NLRP3 inflammasome activation is Nox1-4independent[J].Blood,2010,115(26):5398-5400.
[26]Zhou R,Yazdi A,Menu P,et al.A role for mitochondria in NLRP3 inflammasome activation[J].Nature,2011,469(7329):221-225.
[27]Gill R,Tsung A,Billiar T.Linking oxidative stress to inflammation:toll-like receptors[J].Free Radic Biol Med,2010,48(9):1121-1132.
[28]West A P,Brodsky I E,Rahner C,et al.TLR signalling augments macrophage bactericidal activity through mitochondrial ROS[J].Nature,2011,472(7344):476-480.
[29]Tattoli I,Carneiro L A,Jéhanno M,et al.NLRX1 is a mitochondrial NOD-like receptor that amplifies NF-kappaB and JNK pathways by inducing reactive oxygen species production[J].EMBO Rep,2008,9(3):293-300.
[30]Arnoult D,Soares F,Tattoli I,et al.An N-terminal addressing sequence targets NLRX1 to the mitochondrial matrix[J].J Cell Sci,2009,122(Pt 17):3161-3168.
[31]Hunn J P,Feng C G,Sher A,et al.The immunity-related GTPases in mammals:a fast-evolving cell-autonomous resistance system against intracellular pathogens[J].Mamm Genome,2011,22(1-2):43-54.
[32]Singh S B,Davis A S,Taylor G A,et al.Human IRGM induces autophagy to eliminate intracellular mycobacteria[J].Science,2006,313(5792):1438-1441.
[33]Singh S B,Ornatowski W,Vergne I,et al.Human IRGMregulates autophagy and cell-autonomous immunity functions through mitochondria[J].Nat Cell Biol,2010,12(12):1154-1165.
[34]Garrido C,Galluzzi L,Brunet M,et al.Mechanisms of cytochrome c release from mitochondria[J].Cell Death Differ,2006,13(9):1423-1433.
[35]Wei X,Shao B,He Z,et al.Cationic nanocarriers induce cell necrosis through impairment of Na(+)/K(+)-ATPase and cause subsequent inflammatory response[J].Cell Res,2015,25(2):237-253.
[36]Gurung P,Lukens J R,Kanneganti T D.Mitochondria:diversity in the regulation of the NLRP3 inflammasome[J].Trends Mol Med,2015,21(3):193-201.
[37]White M J,Mcarthur K,Metcalf D,et al.Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production[J].Cell,2014,159(7):1549-1562.
[38]Zhang J Z,Liu Z,Liu J,et al.Mitochondrial DNA induces inflammation and increases TLR9/NF-κB expression in lung tissue[J].Int J Mol Med,2014,33(4):817-824.
[39]Rongvaux A,Jackson R,Harman C C,et al.Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA[J].Cell,2014,159(7):1563-1577.
[40]Sun B,Sundstr?m K,Chew J J,et al.Dengue virus activates cGAS through the release of mitochondrial DNA[J].Sci Rep,2017,7(1):3594.
[41]Aguirre S,Luthra P,Sanchez-Aparicio M T,et al.Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection[J].Nat Microbiol,2017,2:17037.
[42]Nakahira K,Haspel J A,Rathinam V A,et al.Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome[J].Nat Immunol,2011,12(3):222-230.
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