陶冶;任晓峰;

• 1:东北农业大学动物医学学院预防兽医系分子病原学实验室

摘要(Abstract)：

自噬是广泛存在于真核细胞内的一种溶酶体依赖性降解途径,在维持细胞存活、更新、物质再利用和内环境稳定中起着重要作用。目前已经发现大量新的自噬相关基因,同时发现自噬在病毒感染过程中发挥着重要的抗病毒作用:自噬可以将胞质中的病毒转运到溶酶体中,降解病毒;也可以将病毒核酸转运至胞内感受器上激活天然免疫;还可以将病毒抗原递呈给MHCⅡ类分子激活适应性免疫。自噬参与胞内微生物感染具有双重作用。一方面,自噬能够降解入侵的微生物,即以异源吞噬(xenophagy)的方式清除胞内的病原体;另一方面,有些微生物能够通过某些机制逃避自噬而利于自身存活。本文就细胞自噬及其与不同病毒感染关系的最新研究进展进行综述。

关键词(KeyWords)： 细胞自噬;病毒;自噬相关基因

Abstract:

Keywords:

基金项目(Foundation): 教育部新世纪优秀人才项目(NCET-10-0144);; 教育部科技研究重点项目(212038);; 黑龙江省普通高等学校长江学者后备支持计划;; 哈尔滨市科技创新人才研究专项资金(RC2012XK002003)

作者(Authors): 陶冶;任晓峰;

DOI: 10.13242/j.cnki.bingduxuebao.002355

参考文献(References)：

• [1]Czaja M J.Autophagy in health and disease.2.Regual-tion of lipid metabolism and storage by autophagy:pathophysiological implications[J].Am J Physiol CellPhysiol,2010,298(5):973-978.
• [2]Singh R,Kaushik S,Wang Y,et al.Autophagy regulateslipid metabolism[J].Nature,2009,458(7242):1131-1135.
• [3]Levine B,Mizushima N,Virgin H W.Autophagy inimmunity and inflammation[J].Nature,2011,469(7330):323-335.
• [4]Deretic V.Autophagy in immunity and cell-autonomousdefense against intracellular microbes[J].Immunol Rev,2011,240(1):92-104.
• [5]Crotzer V L,Blum J S.Autophagy and intracellularsurveillance:Modulating MHC class II antigen presen-tation with stress[J].Proc Natl Acad Sci USA,2005,102(22):7779-7780.
• [6]Majeski A E,Fred Dice J F.Mechanisms of chaperonemediated autophagy[J].Int J Biochem Cell Biol,2004,36(12):2435-2444.
• [7]Levine B,Yuan J Y.Autophagy in cell death:an inno-cent eonvict[J].Clin Invest,2005,ll5(10):2679-2688.
• [8]Meijer A J,Codogno P.Regulation and role of autoph-agy in mammalian cells[J].Int J Biochem Cell Biol,2004,36(12):2445-2462.
• [9]Mizushima N,Levine B,Cuervo A M,et al.Autophagyfights disease through cellular self digestion[J].Nature,2008,451(7182):1069-1075.
• [10]Dreux M,Chisair F V.Viruses and the autophagy ma-chinery[J].Cell Cycle,2010,1295-1307.
• [11]Klionsky D J,Cuervo A M,Seglen P O.Methods formonitoring autophagy from yeast to human[J].Auto-phagy,2007,3(3):181-206.
• [12]Lockshin R A.Apoptosis,autophagy,and more[J].IntJ Biochem Cell Biol,2004,36(12):2405-2419.
• [13]Klionsky D J,Abeliovich H,Agostinis P,et al.Guidelines for the use and interp retation of assays for-monitoring autophagy in higher eukaryotes[J].Auto-phagy,2008,4(2):151-175.
• [14]Kundu M,Thompson C B.Autophagy:basic princi-ples and relevance to disease[J].Annu Rev Pathol,2008,3:427-455.
• [15]Suzuki K,Ohsumi Y.Molecular machinery of autopha-gosome formation in yeast,Saccharomyces cerevisiae[J].FEBS Lett,2007,581(11):2156-2161.
• [16]Nair U,Klionsky D J.Molecular mechanisms andregulation of specific and nonspecific autophagy path-ways inyeast[J].J Biol Chem,2005,280:41785-41788.
• [17]Yorimitsu T,Klionsky D J.Autophagy:molecularmachinery for self-eating[J].Cell Death Differ,2005,2:1542-1552.
• [18]Klionsky D J,Cregg J M,Dunn W A J,et al.Aunified nomenclature for yeast autophagy related genes[J].Dev Cell,2003,5:539-545.
• [19]Mizushima N.In vivo analysis of autophagy inresponse to nutrient starvation using transgenic miceexpressing a fluorescent autophagosome marker[J].Mol Biol Cell,2004,15(3):1101-1111.
• [20]Mercer C A.A novel,Human Atg13binding protein,Atg1-01,interacts with ULK1 and is essential formacroautophagy[J].Autophagy,2009,5(5):649-662.
• [21]Rubinsztein D C.Potential therapeutic applications ofautophagy[J].Nat Rev Drug Discov,2007,6(4):304-312.
• [22]Itakura E.Atg14and UVRAG:Mutually exclusivesubunits of mammalian Beclin 1-PI3Kcomplexes[J].Autophagy,2009,5(4):534-536.
• [23]Sekito T.Atg17recruits Atg9to organize the pre-auto-phagosomal structure[J].Genes Cells,2009,14(5):525-538.
• [24]Kamada Y,Funakoshi T,Shintani T,et al.Tormedi-ated induction of autophagy via an Apg1protein kinasecomplex[J].J Cell Biol,2000,150:1507-1513.
• [25]Chan E Y,Kir S,Tooze S A.siRNA screening of thekinome identifies ULK1as a multi-domain modulator ofautophagy[J].J Biol Chem,2007,282:25464-25474.
• [26]Young A R,Chan E Y,Hu X W,et al.Starvation andULK1-dependent cycling of mammalian Atg9betweenthe TGN and endosomes[J].J Cell Sci,2006,119:3888-3900.
• [27]Kihara A,Kabeya Y,Ohsumi Y,et al.Beclin-phos-phatidylinositol 3-kinase complex functions at the trans-Golgi network[J].EMBO Rep,2001,2:330-335.
• [28]Tassa A,Roux M P,Attaix D,et al.Class III phos-phoinositide 3-kinase-beclin1 complex mediates theamino acid-dependent regulation of autophagy in C2C12myotubes[J].Biochem J,2003,376:577-586.
• [29]Panaretou C,Domin J,Cockcroft S,et al.Character-ization of p150,an adaptor protein for the human phos-phatidylinositol(PtdIns)3-kinase.Substrate presenta-tion by phosphatidylinositol transfer protein to thep150.Ptdins 3-kinase complex[J].J Biol Chem,1997,272:2477-2485.
• [30]Ohsumi Y.Molecular dissection of autophagy:twoubiquitin-like systems[J].Nat Rev Mol Cell Biol,2001,2:211-216.
• [31]Nakatogawa H,Ichimura Y,Ohsumi Y.Atg8,a ubiq-uitin-like protein required for autophagosome forma-tion,mediates membrane tethering and hemifusion[J].Cell,2007,130:165-178.
• [35]Eskelinen E L,Saftig P.Autophagy:a lysosomaldegradation pathway with a centr-al role in health anddisease[J].Biochim Biophys Acta,2009,1793(4):664-673.
• [32]Talloczy Z,Jiang W,Virgin H W.Regulation ofstarvation and virus induced autophagy by the eIF2alpha kinase signaling pathway[J].Proc Nat.Acad SciUSA,2002,99:190-195.
• [33]Orvedahl A,Alexander D,Talloczy Z,et al.HSV-1ICP34.5confers neurovirulence by targeting the Beclin1autophagy protein[J].Cell Host Microbe,2007,1:23-35.
• [34]Talloczy Z,Virgin H W.PKR dependent autophagicdegradation of herpes simplex virus type1[J].Autoph-agy,2006,2:24-29.
• [35]Alexander D E,Ward S L,Mizushima N,et al.Anal-ysis of the role of autophagy in replication of herpessimplex virus in cell culture[J].J Virol,2007,81:12128-12134.
• [36]Lee J S,Li Q,Lee J Y,et al.FLIP-mediated autoph-agy regulation in cell death control[J].Nat Cell Biol,2009,11:1355-1362.
• [37]Lee D Y,Sugden B.The LMP1oncogene of EBV acti-vates PERK and the unfolded protein response to driveits own synthesis[J].Blood,2008b,111:2280-2289.
• [38]Zhou X,Munger K.Expression of the human papillo-mavirus type 16E7oncoprotein induces an autophagyrelated process and sensitizes normal human keratino-cytes to cell death in response to growth factor depriva-tion[J].Virology,2009,385:192-197.
• [39]Kumar S H,Rangarajan A.Simian virus 40small Tantigen activates AMPK and triggers autophagy toprotect cancer cells from nutrient deprivation[J].JVirol,2009,83:8565-8574.
• [40]Nakashima A,Tanaka N,Tamai K,et al.Survival ofparvovirus B19infected cells by cellular autophagy[J].Virology,2006,349:254-263.
• [41]Sir D,Tian Y,Chen W,et al.The early autophagicpathway is activated by Hepatitis B virus and requiredfor viral DNA replication[J].Proc Natl Acad SciUSA,2010,107(9):4383-4388.
• [42]Tang H,Da L,Mao Y,et al.Hepatitis B virus Xprotein sensitizes cells to starvation induced autophagyvia upregulation of beclin 1expression[J].Hepatology,2009,49:60-71.
• [43]Jackson W T,Giddings T H,Taylor J r,et al.Sub-version of cellular autophagosomal machinery by RNAviruses[J/OL].PLoS Biol,2005,3:e156.
• [44]Suhy D A,Giddings T H,Kirkegaard K.Remodelingthe endoplasmic reticulum by poliovirus infection andby individual viral proteins:an autophagy like originfor virusinduced vesicles[J].J Virol,2000,74:8953-8965.
• [45]Taylor M P,Burgon T B,Kirkegaard K,et al.Role ofmicrotubules in extracellular release of poliovirus[J].JVirol,2009,83:6599-6609.
• [46]Yoon S Y,Ha Y E,Choi J E,et al.Coxsackievirus B4uses autophagy for replication after calpain activation inrat primary neurons[J].J Virol,2008,82:11976-11978.
• [47]Wong J,Zhang J,Si X,et al.Autophagosome sup-ports coxsackievirus B3replication in host cells[J].JVirol,2008,82:9143-9153.
• [48]Ait-Goughoulte M,Kanda T,Meyer K,et al.Hepati-tis C virus genotype 1agrowth and induction of autoph-agy[J].J Virol,2008,82:2241-2249.
• [49]Sir D,Chen W L,Choi J,et al.Induction of incom-plete autophagic response by hepatitis C virus via theunfolded protein response[J].Hepatology,2008a,48:1054-1061.
• [50]Sir D,Liang C,Chen W L,et al.Perturbation of au-tophagic pathway by hepatitis C virus[J].Autophagy,2008b,4:830-831.
• [51]Dreux M,Gastaminza P,Wieland S F,et al.Theautophagy machinery is required to initiate hepatitis Cvirus replication[J].Proc Natl Acad Sci USA,2009,106:14046-14051.
• [52]Tanida I,Fukasawa M,Ueno T,et al.Knockdown ofautophagy-related gene decreases the production ofinfectious hepatitis C virus particles[J].Autophagy,2009,5:937-945.
• [53]Panyasrivanit M,Khakpoor A,Wikan N,et al.Co-lo-calization of constituents of the dengue virus translationand replication machinery with amphisomes[J].J GenVirol,2009,90:448-456.
• [54]Khakpoor A,Panyasrivanit M,Wikan N,et al.A rolefor autophagolysosomes in dengue virus 3production inHepG2cells[J].J Gen Virol,2009,90:1093-1103.
• [55]Prentice E,Jerome W G,Yoshimori T,et al.Corona-virus replication complex formation utilizes componentsof cellular autophagy[J].J Biol Chem,2004,279:10136-10141.
• [56]Zhao Z,Thackray L B,Miller B C,et al.Coronavirusreplication does not require the autophagy gene ATG5[J].Autophagy,2007,3:581-585.
• [57]Gannage M,Dormann D,Albrecht R,et al.Matrixprotein 2of influenza A virus blocks autophagosomefusion with lysosomes[J].Cell Host Microbe,2009,6:367-380.
• [58]Zhou X,Spangle J M,Munger K.Expression of aviral oncoprotein in normal human epithelial cells trig-gers an autophagy related process:is autophagy an“A-chilles’heel”of human cancers?[J]Autophagy,2009a,5(4):578-579.
• [59]Shelly S,Lukinova N,Bambina S,et al.Autophagy isan essential component of Drosophila immunity againstvesicular stomatitis virus[J].Immunity,2009,30:588-598.
• [60]Berkova Z,Crawford S E,Trugnan G,et al,RotavirusNSP4induces a novel vesicular compartment regulatedby calcium and associated with viroplasms[J].J Virol,2006,80:6061-6071.
• [61]Espert L,Varbanov M,Robert-Hebmann V,et al.Differential role of autophagy in CD4Tcells and mac-rophages during X4and R5 HIV-1infection[J/OL].PLoS One,2009,4:e5787.
• [62]Kyei G B,Dinkins C,Davis A S,et al.Autophagypathway intersects with HIV-1biosynthesis and regu-lates viral yields in macrophages[J].J Cell Biol,2009,186:255-268.
• [63]Zhou D,Spector S A.Human immunodeficiency virustype-1infection inhibits autophagy[J].AIDS,2008,22:695-699.
• [64]Brass A L,Dykxhoorn D M,Benita Y,et al.Identifi-cation of host proteins required for HIV infectionthrough a functional genomic screen[J].Science,2008,319:921-926.