三型分泌系统效应蛋白调控细胞凋亡和焦亡的研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2018-0897

摘要/Abstract

摘要： 病原菌感染对人类健康构成了严重的威胁,一类具有三型分泌系统（Type III secretion system,T3SS）的致病菌,可以通过T3SS将效应蛋白“注射”到宿主细胞中,去干扰宿主细胞的多种信号转导通路,从而促进病原菌的增殖和传播。T3SS效应蛋白对宿主的影响被广泛研究,并且不同病原菌采取相似或不同的策略,同一种病原菌的效应蛋白又具有协同或拮抗的功能。综述了T3SS效应蛋白参与宿主细胞凋亡和焦亡信号通路过程中所发挥的功能及分子机制的最新研究进展,并进行了归纳分析,旨在为T3SS效应蛋白的深入研究提供参考和思路,从而进一步推进病原菌致病机制的研究,为防治病原菌提供理论基础。

关键词: 三型分泌系统, 效应蛋白, 细胞凋亡, 细胞焦亡

Abstract: Pathogenic bacterial infection causes a serious threat to human health. Pathogens that harbor a Type III Secretion System（T3SS）can inject effectors into host cells through T3SS and manipulate multiple signaling pathways,thereby facilitating the proliferation and dissemination of pathogens. T3SS effectors play important roles in the signaling pathways involved in apoptosis and pyroptosis of host cells. The effects of T3SS effectors on host have been widely investigated,the effectors of different pathogens exert similarly or differently functions,and the effectors of one species exhibit synergistic or antagonistic roles. Here,we reviewed the latest researches on the function and mechanism of T3SS effectors involved in cell apoptosis and pyroptosis,and made a summary and analysis. It aims to provide references and insight for intensively researching it,thus promoting research on the mechanism of pathogenic bacteria and providing theoretical basis of prevention and treatment of pathogens.

Key words: type III secretion system, effectors, apoptosis, pyroptosis

朱平, 杜力杰, 孟昆, 薛娟, 杨瑾, 李姗. 三型分泌系统效应蛋白调控细胞凋亡和焦亡的研究进展[J]. 生物技术通报, 2019, 35(4): 178-187.

ZHU Ping, DU Li-jie, MENG Kun, XUE Juan, YANG Jin, LI Shan. Research Progress on the Effects of T3SS Effectors on Apoptosis and Pyroptosis of Host Cells[J]. Biotechnology Bulletin, 2019, 35(4): 178-187.

参考文献

[1] Taylor RC, Cullen SP, Martin SJ.Apoptosis:controlled demolition at the cellular level[J]. Nat Rev Mol Cell Biol, 2008, 9(3):231-241.
[2] Faherty CS, Maurelli AT.Staying alive:bacterial inhibition of apoptosis during infection[J]. Trends Microbiol, 2008, 16(4):173-180.
[3] Giogha C, Lung TW, Pearson JS, et al.Inhibition of death receptor signaling by bacterial gut pathogens[J]. Cytokine Growth Factor Rev, 2014, 25(2):235-243.
[4] Li S, Zhang L, Yao Q, et al.Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains[J]. Nature, 2013, 501(7466):242-246.
[5] Pearson JS, Giogha C, Ong SY, et al.A type III effector antagonizes death receptor signalling during bacterial gut infection[J]. Nature, 2013, 501(7466):247-251.
[6] Scott NE, Giogha C, Pollock GL, et al.The bacterial arginine glycosyltransferase effector NleB preferentially modifies Fas-associated death domain protein(FADD)[J]. J Biol Chem, 2017, 292(42):17337-17350.
[7] Blasche S, Mörtl M, Steuber H, et al.The E. coli effector protein NleF is a caspase inhibitor[J]. PLoS One, 2013, 8(3):e58937.
[8] Hemrajani C, Berger CN, Robinson KS, et al.NleH effectors interact with Bax inhibitor-1 to block apoptosis during enteropathogenic Escherichia coli infection[J]. Proc Natl Acad Sci USA, 2010, 107(7):3129-3134.
[9] Baruch K, et al.Metalloprotease type III effectors that specifically cleave JNK and NF-κB[J]. EMBO J, 2011, 30(1):221-231.
[10] Creuzburg K, et al. The type III effector NleD from enteropathogenic Escherichia coli differentiates between host substrates p38 and JNK[J]. Infect Immun, 2017, 85(2). pii:e00620-e00616.
[11] Berger CN, et al. EspZ of enteropathogenic and enterohemorrhagic Escherichia coli regulates type III secretionsystem protein translocation[J]. MBio, 2012, 3(5), pii:e00317-e00312.
[12] Roxas JL, Wilbur JS, Zhang X, et al.The enteropathogenic Escherichia coli-secreted protein EspZ inhibits host cell apoptosis[J]. Infect Immun, 2012, 80(11):3850-3857.
[13] Shames SR, et al.The pathogenic E. coli type III effector EspZ interacts with host CD98 and facilitates host cell prosurvival signaling[J]. Cell Microbiol, 2010, 12(9):1322-1339.
[14] Shames SR, Croxen MA, Deng W, et al.The type III system-secreted effector EspZ localizes to host mitochondria and interacts with the translocase of inner mitochondrial membrane 17b[J]. Infect Immun, 2011, 79(12):4784-4790.
[15] Roxas JL, et al.Enteropathogenic Escherichia coli dynamically regulates EGFR signaling in intestinal epithelial cells[J]. Am J Physiol Gastrointest Liver Physiol, 2014, 307(3):G374-380.
[16] Bergounioux J, Elisee R, Prunier AL, et al.Calpain activation by the Shigella flexneri effector VirA regulates key steps in the formation and life of the bacterium’s epithelial niche[J]. Cell Host Microbe, 2012, 11(3):240-252.
[17] Pendaries C, Tronchère H, Arbibe L, et al.PtdIns5P activates the host cell PI3-kinase/Akt pathway during Shigella flexneri infection[J]. EMBO J, 2006, 25(5):1024-1034.
[18] Mayo LD, Donner DB.A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from thecytoplasm to the nucleus[J]. Proc Natl Acad Sci USA, 2001, 98(20):11598-11603.
[19] Clark CS, Maurelli AT.Shigella flexneri inhibits staurosporine-induced apoptosis in epithelial cells[J]. Infect Immun, 2007, 75(5):2531-2539.
[20] Mou X, et al.Synthetic bottom-up approach reveals the complex interplay of Shigella effectors in regulation of epithelial cell death
[J]. Proc Natl Acad Sci USA, 2018, 115(25):6452-6457.
[21] Knodler LA, Finlay BB, Steele-Mortimer O.The Salmonella effector protein SopB protects epithelial cells from apoptosis by sustained activation of Akt[J]. J Biol Chem, 2005, 10:9058-9064.
[22] Jones RM, Wu H, et al.Salmonella AvrA coordinates suppression of host immune and apoptotic defenses via JNK pathway blockade[J]. Cell Host Microbe, 2008, 3(4):233-244.
[23] Günster RA, Matthews SA, Holden DW, et al. SseK1 and SseK3 type III secretion system effectors inhibit NF-κB signaling and necroptotic cell death in Salmonella-Infected Macrophages[J]. Infect Immun.2017, 85(3), pii:e00010-e00017.
[24] El Qaidi S, Chen K, Halim A, et al.NleB/SseK effectors from Citrobacter rodentium, Escherichia coli, and Salmonella enterica display distinct differences in host substrate specificity[J]. J Biol Chem, 2017, 292(27):11423-11430.
[25] Esposito D, Günster RA, Martino L, et al.Structural basis for the glycosyltransferase activity of the Salmonella effector SseK3[J]. J Biol Chem. 2018, 293(14):5064-5078.
[26] Park JB, Kim YH, Yoo Y, et al.Structural basis for arginine glycosylation of host substrates by bacterial effector proteins[J]. Nat Commun, 2018, 9(1):4283.
[27] Nougayrède JP, Donnenberg MS.Enteropathogenic Escherichia coli EspF is targeted to mitochondria and is required to initiate the mitochondrial death pathway[J]. Cell Microbiol, 2004, 6(11):1097-1111.
[28] Nougayrède JP, Foster GH, Donnenberg MS.Enteropathogenic Escherichia coli effector EspF interacts with host protein Abcf2[J]. Cell Microbiol. 2007, 9(3):680-693.
[29] Samba-Louaka A, Nougayrède JP, Watrin C, et al.The enteropathogenic Escherichia coli effector Cif induces delayed apoptosis in epithelial cells[J]. Infect Immun, 2009, 77(12):5471-5477.
[30] De Rycke J, Comtet E, Chalareng C, et al.Enteropathogenic Escherichia coli O103 from rabbit elicits actin stress fibers and focal adhesions in HeLa epithelial cells, cytopathic effects that are linked to an analog of the locus of enterocyte effacement[J]. Infect Immun, 1997, 65(7):2555-2563.
[31] Morikawa H, et al.The bacterial effector Cif interferes with SCF ubiquitin ligase function by inhibiting deneddylationof Cullin1[J]. Biochem Biophys Res Commun, 2010, 2:268-274.
[32] Nougayrède JP, et al.Type III secretion-dependent cell cycle block caused in HeLa cells by enteropathogenic Escherichia coli O103[J]. Infect Immun, 2001, 11:6785-6795.
[33] Petroski MD, Deshaies RJ.Function and regulation of cullin-RING ubiquitin ligases[J]. Nat Rev Mol Cell Biol, 2005, 6(1):9-20.
[34] Cui J, Yao Q, Li S, et al.Glutamine deamidation and dysfunction of ubiquitin/NEDD8 induced by a bacterial effector family[J]. Science, 2010, 329(5996):1215-1218.
[35] Toro TB, Toth JI, Petroski MD.The cyclomodulin cycle inhibiting factor(CIF)alters cullin neddylation dynamics[J]. J Biol Chem, 2013, 288(21):14716-14726.
[36] Baumann D, et al.Multitalented EspB of enteropathogenic Escherichia coli(EPEC)enters cells autonomously and induces programmed cell death in human monocytic THP-1 cells[J]. Int J Med Microbiol, 2018, 308(3):387-404.
[37] Bruckner S, Rhamouni S, Tautz L, et al.Yersinia phosphatase induces mitochondrially dependent apoptosis of T cells[J]. J Biol Chem. 2005, 280(11):10388-10394.
[38] Pha K, Navarro L.Yersinia type III effectors perturb host innate immune responses[J]. World J Biol Chem, 2016, 7(1):1-13.
[39] Ye Z, Gorman AA, Uittenbogaard AM, et al.Caspase-3 mediates the pathogenic effect of Yersinia pestis YopM in liver of C57BL/6 mice and contributes to YopM’s function in spleen[J]. PLoS One, 2014, 9(11):e110956.
[40] Philip NH, Zwack EE, Brodsky IE.Activation and Evasion of Inflammasomes by Yersinia[J]. Curr Top Microbiol Immunol, 2016, 397:69-90.
[41] Mills SD, Boland A, Sory MP, et al.Yersinia enterocolitica induces apoptosis in macrophages by a process requiring functional type III secretion and translocation mechanisms and involving YopP, presumably acting as an effector protein[J]. Proc Natl Acad Sci USA, 1997, 94(23):12638-12643.
[42] Monack DM, Mecsas J, Ghori N, et al.Yersinia signals macrophages to undergo apoptosis and YopJ is necessary for this cell death[J]. Proc Natl Acad Sci USA, 1997, 94(19):10385-10390.
[43] Orth K, Xu Z, Mudgett MB, et al.Disruption of signaling by Yersinia effector YopJ, a ubiquitin-like protein protease[J]. Science, 2000, 290(5496):1594-1597.
[44] Zhou H, Monack DM, Kayagaki N, et al.Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-kappa B activation[J]. J Exp Med, 2005, 202(10):1327-1332.
[45] Mittal R, Peak-Chew SY, McMahon HT. Acetylation of MEK2 and I kappa B kinase(IKK)activation loop residues by YopJ inhibits signaling[J]. Proc Natl Acad Sci USA, 2006, 103(49):18574-18579.
[46] Mukherjee S, Keitany G, Li Y, et al.Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation[J]. Science, 2006, 312(5777):1211-1214.
[47] Denecker G, et al.Yersinia enterocolitica YopP-induced apoptosis of macrophages involves the apoptotic signaling cascade upstream of bid[J]. J Biol Chem, 2001, 276(23):19706-19714.
[48] Gröbner S, Adkins I, Schulz S, et al.Catalytically active Yersinia outer protein P induces cleavage of RIP and caspase-8 at the level of the DISC independently of death receptors in dendritic cells[J]. Apoptosis, 2007, 12(10):1813-1825.
[49] Viboud GI, Bliska JB.Yersinia outer proteins:role in modulation of host cell signaling responses and pathogenesis[J]. Annu Rev Microbiol, 2005, 59:69-89.
[50] Zhang Y, Bliska JB.Role of Toll-like receptor signaling in the apoptotic response of macrophages to Yersinia infection[J]. Infect Immun, 2003, 71(3):1513-1519.
[51] Jesenberger V, et al.Salmonella-induced caspase-2 activation in macrophages:a novel mechanism in pathogen-mediated apoptosis[J]. J Exp Med, 2000, 192(7):1035-1046.
[52] Kazmierczak BI, Engel JN.Pseudomonas aeruginosa ExoT acts in vivo as a GTPase-activating protein for RhoA, Rac1, and Cdc42[J]. Infect Immun, 2002, 70(4):2198-2205.
[53] Heimer SR, et al.Pseudomonas aeruginosa utilizes the type III secreted toxin ExoS to avoid acidified compartments within epithelial cells[J]. PLoS One, 2013, 8(9):e73111.
[54] Hauser AR.The type III secretion system of Pseudomonas aeruginosa:infection by injection[J]. Nat Rev Microbiol, 2009, 7(9):654-665.
[55] Kaufman MR, Jia J, Zeng L, et al.Pseudomonas aeruginosa mediated apoptosis requires the ADP-ribosylating activity of exoS[J]. Microbiology, 2000, 146(Pt 10):2531-2541.
[56] Jia J, et al.c-Jun NH2-terminal kinase-mediated signaling is essential for Pseudomonas aeruginosa ExoS-induced apoptosis[J]. Infect Immun, 2003, 71(6):3361-3370.
[57] Alaoui-El-Azher M, Jia J, Lian W, et al. ExoS of Pseudomonas aeruginosa induces apoptosis through a Fas receptor/caspase 8-independent pathway in HeLa cells[J]. Cell Microbiol, 2006, 8(2):326-338.
[58] Jansson AL, Yasmin L, Warne P, et al.Exoenzyme S of Pseudomonas aeruginosa is not able to induce apoptosis when cells express activated proteins, such as Ras or protein kinase B/Akt[J]. Cell Microbiol, 2006, 8(5):815-822.
[59] Wood SJ, et al.Pseudomonas aeruginosa ExoT induces mitochondrial apoptosis in target host cells in a manner that depends on its GTPase-activating protein(GAP)domain activity[J]. J Biol Chem, 2015, 290(48):29063-29073.
[60] Kaminski A, Gupta KH, Goldufsky JW, et al.Pseudomonas aeruginosa ExoS induces intrinsic apoptosis in target host cells in a manner that is dependent on its GAP domain activity[J]. Sci Rep, 2018, 8(1):14047.
[61] Yen H, Sugimoto N, Tobe T.Enteropathogenic Escherichia coli uses NleA to inhibit NLRP3 inflammasome activation[J]. PLoS Pathog, 2015, 11(9):e1005121.
[62] Echtenkamp F, Deng W, Wickham ME, et al.Characterization of the NleF effector protein from attaching and effacing bacterial pathogens[J]. FEMS Microbiol Lett, 2008, 281(1):98-107.
[63] Song T, Li K, Zhou W, et al.A Type III effector NleF from EHEC inhibits epithelial inflammatory cell death by targeting caspase-4[J]. Biomed Res Int, 2017, 2017:4101745.
[64] Raymond B, et al.The WxxxE effector EspT triggers expression of immune mediators in an Erk/JNK and NF-κB-dependent manner[J]. Cell Microbiol, 2011, 13(12):1881-1893.
[65] Bergsbaken T, Cookson BT.Macrophage activation redirects Yersinia-infected host cell death from apoptosis to caspase-1-dependent pyroptosis[J]. PLoS Pathog, 2007, 3(11):e161.
[66] Zheng Y, Lilo S, Mena P, et al.YopJ-induced caspase-1 activation in Yersinia-infected macrophages:independent of apoptosis, linked to necrosis, dispensable for innate host defense[J]. PLoS One, 2012, 7(4):e36019.
[67] Philip NH, Dillon CP, Snyder AG, et al.Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB and MAPK signaling[J]. Proc Natl Acad Sci USA, 2014, 111(20):7385-7390.
[68] Ratner D, Orning MP, Starheim KK, et al.Manipulation of interleukin-1β and interleukin-18 production by Yersinia pestis effectors YopJ and YopM and redundant impact on virulence[J]. J Biol Chem, 2016, 291(19):9894-9905.
[69] Schoberle TJ, Chung LK, McPhee JB, et al. Uncovering an Important role for yopJ in the inhibition of caspase-1 in activated macrophages and promoting Yersinia pseudotuberculosis virulence[J]. Infect Immun, 2016, 84(4):1062-1072.
[70] Rosadini CV, Zanoni I, Odendall C, et al.A Single bacterial immune evasion strategy dismantles both MyD88 and TRIF signaling pathways downstream of TLR4[J]. Cell Host Microbe, 2015, 18(6):682-693.
[71] Ratner D, Orning MP, Proulx MK, et al.The Yersinia pestis effector YopM Inhibits pyrin inflammasome activation[J]. PLoS Pathog, 2016, 12(12):e1006035.
[72] Palace SG, Proulx MK, Szabady RL, et al. Gain-of-function analysis reveals important virulence roles for the Yersinia pestis type III secretion system effectors YopJ, YopT,YpkA[J]. Infect Immun, 2018, 86(9). pii:e00318.
[73] Chung LK, et al.IQGAP1 is important for activation of caspase-1 in macrophages and is targeted by Yersinia pestis type III effector YopM[J]. Mbio, 2014, 5(4):e01402-e01414.
[74] LaRock CN, Cookson BT. The Yersinia virulence effector YopM binds caspase-1 to arrest inflammasome assembly and processing[J]. Cell Host Microbe, 2012, 12(6):799-805.
[75] Chung LK, Park YH, Zheng Y, et al.The Yersinia virulence factor YopM hijacks host kinases to inhibit type III effector-triggered activation of the pyrin inflammasome[J]. Cell Host Microbe, 2016, 20(3):296-306.
[76] Park YH, Wood G, Kastner DL, et al.Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS[J]. Nat Immunol, 2016, 17(8):914-921.
[77] Brodsky IE, et al.A Yersinia effector protein promotes virulence by preventing inflammasome recognition of the type III secretion system[J]. Cell Host Microbe, 2010, 7(5):376-387.
[78] Zwack EE, Snyder AG, Wynosky-Dolfi MA, et. al. Inflammasome activation in response to the Yersinia type III secretion system requires hyperinjection of translocon proteins YopB and YopD[J]. Mbio, 2015, 6(1):e02095-e02014.
[79] Thinwa J, Segovia JA, Bose S, et al.Integrin-mediated first signal for inflammasome activation in intestinal epithelial cells[J]. J Immunol, 2014, 193(3):1373-1382.
[80] Müller AJ, Hoffmann C, Galle M, et al.The S. Typhimurium effector SopE induces caspase-1 activation in stromal cells to initiate gut inflammation[J]. Cell Host Microbe, 2009, 6(2):125-136.
[81] Suzuki S, et al.Shigella IpaH7. 8 E3 ubiquitin ligase targets glomu-lin and activates inflammasomes to demolish macrophage[J]. Proc Natl Acad Sci USA, 2014, 111(40):E4254-E4263.
[82] Hermansson AK, Paciello I, Bernardini ML.The orchestra and its maestro:Shigella’s fine-tuning of the inflammasome platforms[J]. Curr Top Microbiol Immunol, 2016, 397:91-115.
[83] Jeon J, Kim YJ, Shin H, et al.T3SS effector ExoY reduces inflammasome-related responses by suppressing bacterial motility and delaying activation of NF-κB and caspase-1[J]. FEBS J, 2017, 284(20):3392-3403.
[84] Duncan MC, Linington RG, Auerbuch V.Chemical inhibitors of the type three secretion system:disarming bacterial pathogens[J]. Antimicrob Agents Chemother, 2012, 56(11):5433-5441.
[85] Lara-Tejero M, Galán JE.Salmonella enterica serovar typhimurium pathogenicity island 1-encodedtype III secretion system translocases mediate intimate attachment tononphagocytic cells[J]. Infect Immun, 2009, 77(7):2635-2642.
[86] Marshall NC, Finlay BB.Targeting the type III secretion system to treat bacterial infections[J]. Expert Opin Ther Targets, 2014, 18(2):137-152.
[87] Gu L, Zhou S, Zhu L, et al.Small-molecule inhibitors of the type III secretion system[J]. Molecules, 2015, 20(9):17659-17674.
[88] Anantharajah A, Buyck JM, Sundin C, et al. Salicylidene acylhydrazides and hydroxyquinolines act as inhibitors of type three secretion systems in Pseudomonas aeruginosa by distinct mechanisms[J]. Antimicrob Agents Chemother, 2017, 61(6). pii:e02566-e02616.
[89] Guo Z, Li X, Li J, et al.Licoflavonol is an inhibitor of the type three secretion system of Salmonella enterica serovar Typhimurium[J]. Biochem Biophys Res Commun, 2016, 477(4):998-1004.