Mpeg1在病原清除中的作用及分子机制

doi:10.16431/j.cnki.1671-7236.2023.04.030

摘要/Abstract

摘要： 巨噬细胞表达基因1(macrophage-expressed gene 1,Mpeg1)编码蛋白是攻膜复合物/穿孔素(membrane attack complex/perforin,MACPF)超家族中的一种穿孔蛋白,广泛存在于动物体内,被认为是现存最古老的MACPF穿孔蛋白。Mpeg1参与宿主先天性免疫,对细菌、病毒和寄生虫均具有杀伤作用。在抗菌免疫中,高表达Mpeg1的细胞可抵御胞内菌、胞外菌、耐酸菌、耐药菌等各种致病菌,这种广谱杀菌活性限制病原菌在宿主体内传播和感染,并间接抑制慢性进行性疾病的发展。在抗寄生虫免疫中,Mpeg1能直接杀伤刺激隐核虫和迈阿密虫等原虫。在抗病毒免疫中,细胞因子诱导表达Mpeg1以抵御病毒感染。近几年的研究表明,Mpeg1还在炎症反应、抗原呈递和一些肿瘤疾病的初步诊断中发挥重要作用。Mpeg1发挥病原清除作用的分子机制为:被诱导表达的Mpeg1通过泛素化在细胞内再分布,最终在溶酶体中与病原体共定位,酸性环境触发Mpeg1在细菌表面打孔,各种抗微生物效应物进入病原菌共同参与病原清除。笔者对Mpeg1编码蛋白的发现、病原清除及其他免疫相关功能及其分子作用机制进行综述,以期为Mpeg1的深入研究和应用提供参考。

关键词: 巨噬细胞表达基因1(Mpeg1); 免疫应答; 病原清除; 杀菌机制; 炎症

Abstract: Macrophage-expressed gene 1 (Mpeg1) protein is a pore-forming protein belonging to the membrane attack complex/perforin (MACPF) superfamily.It is widely found in animals and is considered to be the oldest MACPF pore-forming protein in existence.Mpeg1 is involved in host innate immunity by killing bacteria,viruses and parasites.In antimicrobial immunity,cells with high expression of Mpeg1 can resist variety of pathogens such as intracellular bacteria,extracellular bacteria,acid-resistant bacteria and drug-resistant bacteria.In the host,the spread and infection of pathogens is limited and the development of chronic progressive diseases is inhibited indirectly by this broad-spectrum bactericidal activity.In anti-parasitic immunity,Mpeg1 can directly kill Cryptocaryon irritans,Miamiensis avidus and other protozoa.In antiviral immunity,cytokines induce the expression of Mpeg1 to resist viral infection.The studies in recent years have shown that Mpeg1 plays an important role in inflammatory response,antigen presentation and initial diagnosis of some tumor diseases.The molecular mechanism of Mpeg1 in pathogen clearance:The induced expression of Mpeg1 is redistributed in cells through ubiquitination and finally co-localized with pathogens in lysosomes,the acidic environment triggers Mpeg1 to form pores on the surface of bacteria,various antimicrobial effectors enter pathogens to participate in pathogen clearance.The discovery,pathogen clearance and other immune-related functions,and its molecular mechanisms were reviewed in this article,in order to provide reference for the further research and application of Mpeg1.

Key words: macrophage-expressed gene 1 (Mpeg1); immune response; pathogen clearance; antibacterial mechanism; inflammation

中图分类号:

郭冰玉, 李莉, 李趁, 孔祥会. Mpeg1在病原清除中的作用及分子机制[J]. 中国畜牧兽医, 2023, 50(4): 1584-1592.

GUO Bingyu, LI Li, LI Chen, KONG Xianghui. Role and Molecular Mechanism of Mpeg1 in Pathogen Clearance[J]. China Animal Husbandry and Veterinary Medicine, 2023, 50(4): 1584-1592.

参考文献

[1] BAYLY J C,PANG S S,SPICER B A,et al.Ancient but not forgotten:New insights into MPEG1,a macrophage perforin-like immune effector[J].Frontiers in Immunology,2020,11:581906.
[2] IACOVACHE I,BISCHOFBERGER M,GOOT F G.Structure and assembly of pore-forming proteins[J].Current Opinion in Structural Biology,2010,20(2):241-246.
[3] LUKOYANOVA N,KONDOS S C,FARABELLA I,et al.Conformational changes during pore formation by the perforin-related protein pleurotolysin[J].PLoS Biology,2015,13(2):e1002049.
[4] MUNSON G P,GILBERT R J C,PRADEL G.Editorial:Perforins and cholesterol-dependent cytolysins in immunity and pathogenesis[J].Frontiers in Immunology,2022,13:932502.
[5] MORITA Y C,TSUTSUI T,SATO M,et al.The arabidopsis gene CAD1 controls programmed cell death in the plant immune system and encodes a protein containing a MACPF domain[J].Plant and Cell Physiology,2005,46(6):902-912.
[6] SPILSBURY K,O'MARA M A,WU W M,et al.Isolation of a novel macrophage-specific gene by differential cDNA analysis[J].Blood,1995,85(6):1620-1629.
[7] PANG S S,BAYLY J C,RADJAINIA M,et al.The cryo-EM structure of the acid activatable pore-forming immune effector macrophage-expressed gene 1[J].Nature Communications,2019,10(1):4288.
[8] XIONG P,SHIRATSUCHI M,MATSUSHIMA T,et al.Regulation of expression and trafficking of perforin-2 by LPS and TNF-α[J].Cellular Immunology,2017,320:1-10.
[9] MCCORMACK R M,DE ARMAS L R,SHIRATSUCHI M,et al.Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria[J]. eLife,2015,4:e06508.
[10] BAI F,MCCORMACK R M,HOWER S,et al.Perforin-2 breaches the envelope of phagocytosed bacteria allowing antimicrobial effectors access to intracellular targets[J].The Journal of Immunology,2018,201(9):2710-2720.
[11] WIENS M,KORZHEV M,KRASKO A,et al.Innate immune defense of the sponge Suberites domuncula against bacteria involves a MyD88-dependent signaling pathway:Induction of a perforin-like molecule[J].Journal of Biological Chemistry,2005,280(30):27949-27959.
[12] HE X,ZHANG Y,YU Z.An Mpeg (macrophage expressed gene) from the Pacific oyster Crassostrea gigas:Molecular characterization and gene expression[J].Fish & Shellfish Immunology,2011,30(3):870-876.
[13] GORBUSHIN A M.Membrane attack complex/perforin domain-containing proteins in a dual-species transcriptome of caenogastropoda Littorina littorea and its trematode parasite Himasthla elongata[J].Fish & Shellfish Immunology,2016,54:254-256.
[14] ESTÉVEZ C N,ROMERO A,FIGUERAS A,et al.Involvement of pore-forming molecules in immune defense and development of the Mediterranean mussel (Mytilus galloprovincialis)[J].Developmental & Comparative Immunology,2011,35(10):1017-1031.
[15] BATHIGE S D N K,UMASUTHAN N,WHANG I,et al.Antibacterial activity and immune responses of a molluscan macrophage expressed gene-1 from disk abalone,Haliotis discus discus[J].Fish & Shellfish Immunology,2014,39(2):263-272.
[16] WANG G D,ZHANG K F,ZHANG Z P,et al.Molecular cloning and responsive expression of macrophage expressed gene from small abalone Haliotis diversicolor supertexta[J].Fish & Shellfish Immunology,2008,24(3):346-359.
[17] WANG K J,REN H L,XU D D,et al.Identification of the up-regulated expression genes in hemocytes of variously colored abalone (Haliotis diversicolor Reeve,1846) challenged with bacteria[J].Developmental & Comparative Immunology,2008,32(11):1326-1347.
[18] KEMP I K,COYNE V E.Identification and characterisation of the Mpeg1 homologue in the South African abalone,Haliotis midae[J].Fish & Shellfish Immunology,2011,31(6):754-764.
[19] TRAYLOR K N,VANDEPAS L E,BROWNE W E.Still enigmatic:Innate immunity in the ctenophore Mnemiopsis leidyi[J].Integrative and Comparative Biology,2019,59(4):811-818.
[20] CHOI K M,CHO D H,JOO M S,et al.Functional characterization and gene expression profile of perforin-2 in starry flounder (Platichthys stellatus)[J].Fish & Shellfish Immunology,2020,107:511-518.
[21] NI L Y,HAN Q,CHEN H P,et al.Grouper (Epinephelus coioides) Mpeg1s:Molecular identification,expression analysis,and antimicrobial activity[J].Fish & Shellfish Immunology,2019,92:690-697.
[22] NI L Y,CHEN H P,HAN R,et al.Distribution of Mpeg1⁺ cells in healthy grouper (Epinephelus coioides) and after Cryptocaryon irritans infection[J].Fish & Shellfish Immunology,2020,104:222-227.
[23] BENARD E L,RACZ P I,ROUGEOT J,et al.Macrophage-expressed perforins mpeg1 and Mpeg1.2 have an anti-bacterial function in zebrafish[J].Journal of Innate Immunity,2015,7(2):136-152.
[24] ELLETT F,PASE L,HAYMAN J,et al.Mpeg1 promoter transgenes direct macrophage-lineage expression in zebrafish[J].Blood,2011,117(4):E49-E56.
[25] MCCORMACK R,PODACK E R.Perforin-2/Mpeg1 and other pore-forming proteins throughout evolution[J].Journal of Leukocyte Biology,2015,98:761-768.
[26] CONNELLY M T,MCRAE C J,LIU P J,et al.Lipopolysaccharide treatment stimulates Pocillopora coral genotype-specific immune responses but does not alter coral-associated bacteria communities[J].Developmental & Comparative Immunology,2020,109:103717.
[27] YOUNG B D,SERRANO X M,ROSALES S M,et al.Innate immune gene expression in Acropora palmata is consistent despite variance in yearly disease events[J].PLoS One,2020,15(10):e0228514.
[28] WALTERS B M,CONNELLY M T,YOUNG B,et al.The complicated evolutionary diversification of the Mpeg-1/perforin-2 family in cnidarians[J].Frontiers in Immunology,2020,11:1690.
[29] KONDOS S C,HATFALUDI T,VOSKOBOINIK I,et al.The structure and function of mammalian membrane-attack complex/perforin-like proteins[J].Tissue Antigens,2010,76(5):341-351.
[30] D'ANGELO M E,DUNSTONE M A,WHISSTOCK J C,et al.Perforin evolved from a gene duplication of MPEG1,followed by a complex pattern of gene gain and loss within Euteleostomi[J].BMC Evolutionary Biology,2012,12(1):59.
[31] HOWER S,MCCORMACK R,BARTRA S S,et al.LPS modifications and AvrA activity of Salmonella enterica serovar Typhimurium are required to prevent perforin-2 expression by infected fibroblasts and intestinal epithelial cells[J].Microbial Pathogenesis,2021,154:104852.
[32] MCCORMACK R,DE A L R,SHIRATSUCHI M,et al.Inhibition of intracellular bacterial replication in fibroblasts is dependent on the perforin-like protein (perforin-2) encoded by macrophage-expressed gene 1[J].Journal of Innate Immunity,2013,5(2):185-194.
[33] MERSELIS L C,JIANG S Y,NELSON S F,et al.MPEG1/perforin-2 haploinsufficiency associated polymicrobial skin infections and considerations for interferon-γ therapy[J].Frontiers in Immunology. 2020,11:601584.
[34] PASTAR I,SAWAVA A P,MARJANOVIC J,et al.Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression[J].The Journal of Clinical Investigation,2021,131(24):e133727.
[35] MCCORMACK R M,SZYMANSKI E P,HSU A P,et al.MPEG1/perforin-2 mutations in human pulmonary nontuberculous mycobacterial infections[J].JCI Insight,2017,2(8):e89635.
[36] HUNG L Y,TANAKA Y,HERBINE K,et al.Cellular context of IL-33 expression dictates impact on anti-helminth immunity[J].Science Immunology,2020,5(53):eabc6259.
[37] RENAULT T,FAURY N,BARBOSA S V,et al.Suppression substractive hybridisation (SSH) and Real time PCR reveal differential gene expression in the Pacific cupped oyster,Crassostrea gigas,challenged with Ostreid herpesvirus 1[J].Developmental & Comparative Immunology,2011,35(7):725-735.
[38] MCCORMACK R,HUNTE R,PODACK E R, et al.An essential role for perforin-2 in type Ⅰ IFN signaling[J].The Journal of Immunology,2020,204(8):2242-2256.
[39] 崔红颖,要萌萌,宋学琴,等.Mdx小鼠骨骼肌中炎症反应和Mpeg1的表达[J].中风与神经疾病杂志,2016,33(8):711-714. CUI H Y,YAO M M,SONG X Q,et al.The inflammation and the expression of Mpeg1 in Mdx mice skeletal muscle[J].Journal of Apoplexy and Nervous Diseases,2016,33(8):711-714.(in Chinese)
[40] JIANG P,YUAN G H,JIANG B R,et al.Effects of microplastics (MPs) and tributyltin (TBT) alone and in combination on bile acids and gut microbiota crosstalk in mice[J].Ecotoxicology and Environmental Safety,2021,220:112345.
[41] FRASCA D,DIAZ A,ROMERO M,et al.Impaired B cell function in mice lacking perforin-2[J].Frontiers in Immunology,2020,11:328.
[42] SHEN R,XU P P,WANG N,et al.Influence of oncogenic mutations and tumor microenvironment alterations on extranodal invasion in diffuse large B-cell lymphoma[J].Clinical and Translational Medicine,2020,10(7):e221.
[43] QIN W,FU D,SHI Q,et al.Molecular heterogeneity in localized diffuse large B-cell lymphoma[J].Frontiers in Oncology,2021,11:638757.
[44] HUANG C,SU X,ZHOU D L,et al.A diagnostic and predictive lncRNA lnc-MPEG1-1 promotes the proliferation and metastasis of papillary thyroid cancer cells by occupying miR-766-5p[J].Molecular Therapy-Nucleic Acids,2022,28:408-422.
[45] EBRAHIMNEZHADDRZI S,BIRD C H,ALLISON C C,et al.Mpeg1 is not essential for antibacterial or antiviral immunity,but is implicated in antigen presentation[J].Immunology and Cell Biology,2022,100(7):529-546.
[46] CHALBATANI G M,MOMENI S A,MOHAMMADI HADLOO M H,et al.Comprehensive analysis of ceRNA networks to determine genes related to prognosis,overall survival,and immune infiltration in clear cell renal carcinoma[J].Computers in Biology and Medicine,2022,141:105043.
[47] MCCORMACK R M,LYAPICHEV K,OLSSON M L,et al.Enteric pathogens deploy cell cycle inhibiting factors to block the bactericidal activity of perforin-2[J]. eLife,2015,4:e06505.
[48] MERSELIS L C,RIVAS Z P,MUNSON G P.Breaching the bacterial envelope:The pivotal role of perforin-2 (MPEG1) within phagocytes[J].Frontiers in Immunology,2021,12:597951.
[49] NI T,JIAO F,YU X,et al.Structure and mechanism of bactericidal mammalian perforin-2,an ancient agent of innate immunity[J].Science Advances,2020,6(5):eaax8286.
[50] BOURA E,HURLEY J H.Structural basis for membrane targeting by the MVB12-associated β-prism domain of the human ESCRT-Ⅰ MVB12 subunit[J].Proceedings of the National Academy of Sciences,2012,109(6):1901-1906.
[51] JIAO F,DEHEZ F,NI T,et al.Perforin-2 clockwise hand-over-hand pre-pore to pore transition mechanism[J].Nature Communications,2022,13(1):5039.
[52] SERNA M,GILES J L,MORGAN B P,et al.Structural basis of complement membrane attack complex formation[J].Nature Communications,2016,7(1):10587.
[53] KRISHNAKUMAR R,CRAIG M,IMLAY J A,et al.Differences in enzymatic properties allow SodCⅠ but not SodCⅡ to contribute to virulence in Salmonella enterica serovar Typhimurium strain 14028[J].Journal of Bacteriology,2004,186(16):5230-5238.