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作为生物体基本的结构与功能单位,细胞具有严格的代谢体系,以适应不同的环境条件、维持机体稳态与能量平衡。细胞自噬(autophagy)是一种高度保守的分解代谢途径,通过降解不必要的、不需要的或功能失调的细胞成分,包括半衰期较长的或错误折叠的蛋白质,甚至是损伤的细胞器,如线粒体、核糖体、内质网等,严密调控细胞稳态[1]。通常情况下,自噬通路的激活是由于细胞处于营养缺乏的状态,自噬体(autophagosome)包裹细胞质组分,通过分解代谢为细胞提供营养物质,此时自噬是没有选择性的,这种非选择性的自噬也被认为是经典的自噬途径(canonical autophagy)。近年来,许多研究表明,细胞倾向于有选择地借助自噬降解底物,胞内外的各种刺激因素,如细胞器受损、有毒蛋白质的聚集或氧化应激,均可诱导细胞自噬[2]。根据包裹底物的不同,具有底物选择性的自噬又被分为线粒体自噬(mitophagy)、聚集体自噬(aggrephagy)、过氧化物酶体自噬(pexophagy)、病原体自噬(xenophagy)等。病原体自噬,即细菌等病原微生物入侵时,自噬体包裹入侵的病原后与溶酶体融合,清除胞内细菌[3]。同时,根据自噬体的形成过程及运送方式的不同,可将细胞自噬分为3类:①巨自噬(macroautophagy):形成具有双层膜结构的自噬体包裹胞内物质。一般情况下所说的自噬指的是巨自噬[4]。②微自噬(microautophagy):溶酶体或液泡表面的形变直接吞没胞浆成分[5]。③分子伴侣介导的自噬(chaperone-mediated autophagy, CMA):具有KEFRQ样基序的蛋白在分子伴侣(如HSP70)的帮助下,通过LAMP-2A转运体直接转运到溶酶体[6]。
自噬在清除胞内废物、维持细胞能量水平、应对环境变化等方面都发挥着重要的作用。细菌感染细胞时,通过多种途径激活病原体自噬。细胞接受到自噬诱导信号后,在胞浆中形成多个自噬体膜发生中心,形成杯状的吞噬泡(phagophore),随后吞噬泡的双层膜结构延伸,包裹胞浆内的目标组分,封闭后形成300~900 nm的自噬体,微管相关蛋白轻链3(microtubule-associated proteins 1A and 1B, MAP1LC3/LC3)由胞浆(LC3-I)转位到自噬体膜(LC3-II)。目前认为,自噬体膜并不直接来源于高尔基体或内质网,而是在包浆中重新生成的,具体机制尚不清楚。成熟的自噬体与溶酶体(lysosome)融合形成自噬溶酶体(autolysosome),在自噬溶酶体中,内容物被降解、回收。病原体自噬激活后,一方面通过对包裹细菌的降解限制胞内细菌的增殖,另一方面,包裹细菌的自噬体也为细菌提供了便宜的生存环境,许多细菌进化出在自噬体中增殖后通过破坏自噬体膜逃逸细胞自噬的机制。本文将从细菌激活自噬途径、自噬反应通路、细菌逃逸或利用细胞自噬机制以及利用自噬治疗感染性疾病方法5个方面展开,深入阐明细菌感染与细胞自噬的动态平衡机制,以期为后续的细胞自噬研究提供资料与参考。
Advances in autophagy induced by bacterial infection
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摘要: 细胞内的细菌清除和增殖是细菌感染和细胞自噬之间的博弈:细胞借助自噬系统识别、清除胞内细菌;细菌进化出不同的逃逸机制,抑制、利用细胞自噬,促进自身增殖。针对细菌感染与细胞自噬之间的复杂关系,对细菌激活细胞自噬途径、自噬反应通路、细菌与自噬的相互作用以及感染性疾病治疗中的自噬调节进行了总结,综述了现阶段病原体自噬及细菌逃逸、利用细胞自噬的研究进展。Abstract: The autophagy pathway activated by bacteria has two faces in maintaining the dynamic balance between intracellular bacterial removal and proliferation. On the one hand, cells recognize and remove intracellular bacteria via autophagy; on the other hand, bacteria evolve various escape mechanisms to inhibit and utilize autophagy to promote their own proliferation. A comprehensive summary was made of the complex relationship between bacterial infection and autophagy, involving the activation of autophagic pathways by bacteria, autophagic response pathways, the interaction between bacteria and autophagy, and the regulation of autophagy in the treatment of infectious diseases to review recent advances in bacterial infection and autophagy, as well as the utilization of autophagy, so as to provide reference for subsequent autophagy exploration.
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Key words:
- autophagy /
- bacterial infection /
- immune escape
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[1] KUMA A, KOMATSU M, MIZUSHIMA N. Autophagy-monitoring and autophagy-deficient mice [J]. Autophagy, 2017, 13(10): 1619 − 1628. doi: 10.1080/15548627.2017.1343770 [2] 张宏, 张慧. 多细胞生物自噬的分子机制和生理功能[J]. 安徽大学学报(自然科学版), 2018, 42(5): 105 − 114. [3] KWON D H, SONG H K. A Structural view of xenophagy, a battle between host and microbes [J]. Mol Cells, 2018, 41(1): 27 − 34. [4] FENG Y, HE D, YAO Z, et al. The machinery of macroautophagy [J]. Cell Res, 2014, 24(1): 24 − 41. doi: 10.1038/cr.2013.168 [5] LI W W, LI J, BAO J K. Microautophagy: lesser-known self-eating [J]. Cell Mol Life Sci, 2012, 69(7): 1125 − 1136. doi: 10.1007/s00018-011-0865-5 [6] DICE J F. Chaperone-mediated autophagy [J]. Autophagy, 2007, 3(4): 295 − 299. doi: 10.4161/auto.4144 [7] WANG Z, LI C. Xenophagy in innate immunity: A battle between host and pathogen [J]. Dev Comp Immunol, 2020, 109: 103693. doi: 10.1016/j.dci.2020.103693 [8] LI S, HE J, XU H, et al. Autophagic activation of IRF-1 aggravates hepatic ischemia-reperfusion injury via JNK signaling [J]. MedComm, 2021, 2(1): 91 − 100. [9] DERETIC V. Autophagy as an innate immunity paradigm: expanding the scope and repertoire of pattern recognition receptors [J]. Curr Opin Immunol, 2012, 24(1): 21 − 31. doi: 10.1016/j.coi.2011.10.006 [10] LEE Y J, KIM J K, JUNG C H, et al. Chemical modulation of SQSTM1/p62-mediated xenophagy that targets a broad range of pathogenic bacteria [J]. Autophagy, 2022, 18(12): 2926 − 2945. doi: 10.1080/15548627.2022.2054240 [11] TURCO E, SAVOVA A, GERE F, et al. Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation [J]. Nat Commun, 2021, 12(1): 5212. doi: 10.1038/s41467-021-25572-w [12] MATTHEW T S, ELISABETH G F, JESSICA T, et al. Complement C3 drives autophagy-dependent restriction of cyto-invasive bacteria [J]. Cell Host & Microbe, 2018, 23(5): 644 − 652. [13] DI RIENZO M, ROMAGNOLI A, ANTONIOLI M, et al. TRIM proteins in autophagy: selective sensors in cell damage and innate immune responses [J]. Cell Death Differ, 2020, 27(3): 887 − 902. doi: 10.1038/s41418-020-0495-2 [14] FISCHER T D, WANG C, PADMAN B S, et al. STING induces LC3B lipidation onto single-membrane vesicles via the V-ATPase and ATG16L1-WD40 domain [J]. J Cell Biol, 2020, 219(12): .1 − 17. [15] INOMATA M, XU S, CHANDRA P, et al. Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging [J]. Proc Natl Acad Sci U S A, 2020, 117(52): 33561 − 33569. doi: 10.1073/pnas.2015368117 [16] NOWACKA-WOSZUK J, MACKOWSKI M, MANTAJ W, et al. Equine STX17 intronic triplication confirmed by droplet digital PCR analysis of its breakpoints [J]. Anim Genet, 2021, 52(4): 567 − 568. doi: 10.1111/age.13073 [17] GAO N, YANG Y, LIU S, et al. Gut-derived metabolites from dietary tryptophan supplementation quench intestinal inflammation through the AMPK-SIRT1-autophagy pathway [J]. J Agric Food Chem, 2022, 70(51): 16080 − 16095. doi: 10.1021/acs.jafc.2c05381 [18] PRAJSNAR T K, SERBA J J, DEKKER B M, et al. The autophagic response to Staphylococcus aureus provides an intracellular niche in neutrophils [J]. Autophagy, 2021, 17(4): 888 − 902. doi: 10.1080/15548627.2020.1739443 [19] TINGTING W, TIANQI F, XINYU W, et al. Amentoflavone attenuates Listeria monocytogenes pathogenicity through an LLO-dependent mechanism [J]. Br J Pharmacol, 2022, 179(14): 3839 − 3858. doi: 10.1111/bph.15827 [20] BOUJEMAA-PATERSKI R, GOUIN E, HANSEN G, et al. Listeria protein ActA mimics WASp family proteins: it activates filament barbed end branching by Arp2/3 complex [J]. Biochemistry, 2001, 40(38): 11390 − 11404. doi: 10.1021/bi010486b [21] LIN C Y, NOZAWA T, MINOWA N A, et al. Autophagy receptor tollip facilitates bacterial autophagy by recruiting galectin-7 in response to Group A streptococcus infection[J]. Frontiers in Cellular and Infection Microbiology, 2020(10). doi: 10.3389/fcimb.2020.583137. [22] BIRMINGHAM C L, BRUMELL J H. Autophagy recognizes intracellular Salmonella enterica serovar Typhimurium in damaged vacuoles [J]. Autophagy, 2006, 2(3): 156 − 158. doi: 10.4161/auto.2825 [23] CAMPBELL-VALOIS F X, SACHSE M, SANSONETTI P J, et al. Escape of actively secreting Shigella flexneri from ATG8/LC3-Positive vacuoles formed during cell-to-cell spread is facilitated by IcsB and VirA [J]. MBio, 2015, 6(3): 2514 − 2567. [24] KELLER M D, CHING K L, LIANG F X, et al. Decoy exosomes provide protection against bacterial toxins [J]. Nature, 2020, 579(7798): 260 − 264. doi: 10.1038/s41586-020-2066-6 [25] MA L, LI W, ZHANG Y, et al. FLT4/VEGFR3 activates AMPK to coordinate glycometabolic reprogramming with autophagy and inflammasome activation for bacterial elimination [J]. Autophagy, 2022, 18(6): 1385 − 1400. doi: 10.1080/15548627.2021.1985338 [26] JIN T, HE P, YANG R, et al. CHI3L1 promotes Staphylococcus aureus-induced osteomyelitis by activating p38/MAPK and Smad signaling pathways [J]. Exp Cell Res, 2021, 403(1): 112596. doi: 10.1016/j.yexcr.2021.112596 [27] DINIC M, JAKOVLJEVIC S, DOKIC J, et al. Probiotic-mediated p38 MAPK immune signaling prolongs the survival of Caenorhabditis elegans exposed to pathogenic bacteria [J]. Sci Rep, 2021, 11(1): 21258. doi: 10.1038/s41598-021-00698-5 [28] XU Y, CHENG S, ZENG H, et al. ARF GTPases activate Salmonella effector SopF to ADP-ribosylate host V-ATPase and inhibit endomembrane damage-induced autophagy [J]. Nat Struct Mol Biol, 2022, 29(1): 67 − 77. doi: 10.1038/s41594-021-00710-6 [29] CHANG F, LI N, YAN K, et al. Luminal/extracellular domains of chimeric CI-M6PR-C proteins interfere with their retrograde endosome-to-TGN trafficking in the transient expression system [J]. J Biomed Res, 2018, 32(4): 245 − 256. doi: 10.7555/JBR.32.20180044 [30] RABINOVICH-NIKITIN I, COGAN R C, KIRSHENBAUM L A. Attenuation of obesity cardiomyopathy by Ulk1/Rab9 mediated alternative mitophagy [J]. Circ Res, 2021, 129(12): 1122 − 1124. doi: 10.1161/CIRCRESAHA.121.320365 [31] JALAGADUGULA G, MAO G, GOLDFINGER L E, et al. Defective RAB31-mediated megakaryocytic early endosomal trafficking of VWF, EGFR, and M6PR in RUNX1 deficiency [J]. Blood Adv, 2022, 13,(17): 5100 − 5112. [32] CAPURRO M I, PRASHAR A, JONES N L. MCOLN1/TRPML1 inhibition - a novel strategy used by Helicobacter pylori to escape autophagic killing and antibiotic eradication therapy in vivo [J]. Autophagy, 2020, 16(1): 169 − 170. doi: 10.1080/15548627.2019.1677322 [33] VASUDEVAN S, THAMIL S G, BHASKARAN S, et al. Reciprocal cooperation of Type A procyanidin and nitrofurantoin against multi-drug resistant (MDR) UPEC: A pH-dependent study [J]. Front Cell Infect Microbiol, 2020, 10: 421. doi: 10.3389/fcimb.2020.00421 [34] 段灵涛, 祝一鸣, 何九卿, 等. 真菌细胞自噬的研究进展[J]. 热带生物学报, 2021, 12(2): 253 − 260. doi: 10.15886/j.cnki.rdswxb.2021.02.015 [35] JAN H M, CHEN Y C, YANG T C, et al. Cholesteryl alpha-D-glucoside 6-acyltransferase enhances the adhesion of Helicobacter pylori to gastric epithelium [J]. Commun Biol, 2020, 3(1): 120. doi: 10.1038/s42003-020-0855-y [36] LAI C H, HUANG J C, CHENG H H, et al. Helicobacter pylori cholesterol glucosylation modulates autophagy for increasing intracellular survival in macrophages [J]. Cell Microbiol, 2018, 20(12): e12947. doi: 10.1111/cmi.12947 [37] OMOTADE T O, ROY C R. Legionella pneumophila excludes autophagy adaptors from the ubiquitin-labeled vacuole in which it resides [J]. Infect Immun, 2020, 88(8): e00793 − 19. doi: 10.1128/IAI.00793-19 [38] CHOY A, ROY C R. Autophagy and bacterial infection: an evolving arms race [J]. Trends Microbiol, 2013, 21(9): 451 − 456. doi: 10.1016/j.tim.2013.06.009 [39] LEMARIGNIER M, PIZARRO-CERDA J. Autophagy and intracellular membrane trafficking subversion by pathogenic Yersinia species [J]. Biomolecules, 2020, 10(12): 1637. doi: 10.3390/biom10121637 [40] PUJOL C, KLEIN K A, ROMANOV G A, et al. Yersinia pestis can reside in autophagosomes and avoid xenophagy in murine macrophages by preventing vacuole acidification [J]. Infect Immun, 2009, 77(6): 2251 − 2261. doi: 10.1128/IAI.00068-09 [41] ZHANG L, YU S, NING X, et al. A LysR transcriptional regulator manipulates macrophage autophagy flux during brucella infection [J]. Front Cell Infect Microbiol, 2022, 12: 858173. doi: 10.3389/fcimb.2022.858173 [42] MUNOZ-SANCHEZ S, VAN DER VAART M, MEIJER A H. Autophagy and Lc3-associated phagocytosis in zebrafish models of bacterial infections [J]. Cells, 2020, 9(11): 2372. doi: 10.3390/cells9112372 [43] GUNAWAN M, LOW C, NEO K, et al. The role of autophagy in chemical proteasome inhibition model of retinal degeneration [J]. Int J Mol Sci, 2021, 22(14): 7271. doi: 10.3390/ijms22147271 [44] DEVIS-JAUREGUI L, ERITJA N, DAVIS M L, et al. Autophagy in the physiological endometrium and cancer [J]. Autophagy, 2021, 17(5): 1077 − 1095. doi: 10.1080/15548627.2020.1752548 [45] VAN ROEDEN S E, BLEEKER-ROVERS C P, DE REGT M, et al. Treatment of chronic Q fever: Clinical efficacy and toxicity of antibiotic regimens [J]. Clin Infect Dis, 2018, 66(5): 719 − 726. doi: 10.1093/cid/cix886 [46] GUERRERO-BUSTAMANTE C A, DEDRICK R M, GARLENA R A, et al. Toward a phage cocktail for tuberculosis: Susceptibility and tuberculocidal action of mycobacteriophages against diverse mycobacterium tuberculosis strains [J]. mBio, 2021, 12(3): 921 − 937. doi: 10.1128/mBio.00973-21 [47] RENNA M, RUBINSZTEIN D C. Macroautophagy without LC3 conjugation? [J]. Cell Res, 2017, 27(1): 5 − 6. doi: 10.1038/cr.2016.143 [48] CONWAY K L, KUBALLA P, SONG J H, et al. Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection [J]. Gastroenterology, 2013, 145(6): 1347 − 1357. doi: 10.1053/j.gastro.2013.08.035