弓形虫蛋白质翻译后修饰研究进展

doi:10.11843/j.issn.0366-6964.2021.011.001

摘要/Abstract

摘要： 弓形虫是一种复杂的单细胞原生动物寄生虫，通过入侵宿主细胞、分裂和诱导宿主细胞破裂等一系列的过程，在温血动物体内进行增殖。弓形虫的生物学特征受基因组、表观遗传及转录等多种因素的调控。蛋白质翻译后修饰（protein post-translational modifications，PTMs），如磷酸化、泛素化、巴豆酰化、棕榈酰化、琥珀酰化、乙酰化、甲基化、糖基化和二羟基异丁酰化等，是弓形虫调节对细胞外刺激的反应和生命周期转变的主要机制之一。弓形虫蛋白质翻译后修饰通过改变靶蛋白的定位、结构、活性、蛋白质-蛋白质相互作用等增加蛋白质的复杂性和多样性，从而在虫体生命周期的任何时间点都可以发挥至关重要的作用。在这篇综述中，作者重点对弓形虫蛋白质翻译后修饰进行简要总结，以期为深入研究弓形虫的生物学特征奠定基础。

关键词: 弓形虫, 顶复门寄生虫, 蛋白质翻译后修饰, 表观遗传学

Abstract: Toxoplasma gondii, as one of the Apicomplexa phylum parasites, which repeatedly goes through a cycle of invasion, division and induction of host cell rupture, which is an obligatory process for proliferation inside warm-blooded animals. It is known that the biology of the parasite is controlled by a variety of factors ranging from genomic to epigenetic to transcriptional regulation. One of the mechanisms by which Toxoplasma gondii likely regulates responses to extracellular stimuli and life cycle transitions is through protein post-translational modifications (PTMs). PTMs, such as phosphorylation, ubiquitination, crotonylation, palmitoylation, succinylation, acetylation, methylation, glycosylation and 2-hydroxyisobutyrylation, regulate numerous metabolic processes and every aspect of T. gondii biology. PTMs can play a vital role in any time of their lifespan, which through alterations of target protein localization, structure, activity, protein-protein interactions, among other functions, dramatically increase proteome complexity and diversity. In this review, we highlight the advanced insights into PTMs in T. gondii and their crosstalk, laying a foundation for in-depth study on the biological characteristics of T. gondii.

Key words: Toxoplasma gondii, apicomplexan parasite, protein posttranslational modifications, epigenetic

中图分类号:

S852.72

尹德琦, 魏子巍, 张义伟, 桑晓宇, 杨娜, 冯颖, 陈冉, 姜宁. 弓形虫蛋白质翻译后修饰研究进展[J]. 畜牧兽医学报, 2021, 52(11): 2995-3005.

YIN Deqi, WEI Ziwei, ZHANG Yiwei, SANG Xiaoyu, YANG Na, FENG Ying, CHEN Ran, JIANG Ning. Research Progress in Protein Post-translational Modifications of Toxoplasma gondii[J]. Acta Veterinaria et Zootechnica Sinica, 2021, 52(11): 2995-3005.

参考文献 74

[1]	MARINO N D, PANAS M W, FRANCO M, et al. Identification of a novel protein complex essential for effector translocation across the parasitophorous vacuole membrane of Toxoplasma gondii[J].PLoS Pathog, 2018, 14(1):e1006828.
[2]	KWONG W K, DEL CAMPO J, MATHUR V, et al. A widespread coral-infecting apicomplexan with chlorophyll biosynthesis genes[J].Nature, 2019, 568(7750):103-107.
[3]	WANG Z D, LIU H H, MA Z X, et al. Toxoplasma gondii Infection in immunocompromised patients:a systematic review and meta-analysis[J].Front Microbiol, 2017, 8:389.
[4]	ODENIRAN P O, OMOLABI K F, ADEMOLA I O.Risk factors associated with seropositivity for Toxoplasma gondii in population-based studies among immunocompromised patients (pregnant women, HIV patients and children) in West African countries, Cameroon and Gabon:a meta-analysis[J].Acta Trop, 2020, 209:105544.
[5]	VALENTINI P, BUONSENSO D, BARONE G, et al. Spiramycin/cotrimoxazole versus pyrimethamine/sulfonamide and spiramycin alone for the treatment of toxoplasmosis in pregnancy[J].J Perinatol, 2015, 35(2):90-94.
[6]	MACEK B, FORCHHAMMER K, HARDOUIN J, et al. Protein post-translational modifications in bacteria[J].Nat Rev Microbiol, 2019, 17(11):651-664.
[7]	YAKUBU R R, WEISS L M, DE MONERRI N C S.Post-translational modifications as key regulators of apicomplexan biology:insights from proteome-wide studies[J].Mol Microbiol, 2018, 107(1):1-23.
[8]	YIN D Q, JIANG N, ZHANG Y, et al. Global lysine crotonylation and 2-hydroxyisobutyrylation in phenotypically different Toxoplasma gondii parasites[J].Mol Cell Proteom, 2019, 18(11):2207-2224.
[9]	KUMAR R, MEHTA D, MISHRA N, et al. Role of host-mediated post-translational modifications (PTMs) in RNA virus pathogenesis[J].Int J Mol Sci, 2020, 22(1):323.
[10]	LIU J, QIAN C, CAO X T.Post-translational modification control of innate immunity[J].Immunity, 2016, 45(1):15-30.
[11]	刘静, 李亚超, 周梦岩, 等. 植物蛋白质翻译后修饰组学研究进展[J].生物技术通报, 2021, 37(1):67-76.LIU J, LI Y C, ZHOU M Y, et al. Advances in the studies of plant protein post-translational modification[J].Biotechnology Bulletin, 2021, 37(1):67-76.(in Chinese)
[12]	YAKUBU R R, DE MONERRI N C S, NIEVES E, et al. Comparative monomethylarginine proteomics suggests that protein arginine methyltransferase 1(PRMT1) is a significant contributor to arginine monomethylation in Toxoplasma gondii[J].Mo Cell Proteom, 2017, 16(4):567-580.
[13]	DE MONERRI N C S, YAKUBU R R, CHEN A L, et al. The ubiquitin proteome of Toxoplasma gondii reveals roles for protein ubiquitination in cell-cycle transitions[J].Cell Host Microbe, 2015, 18(5):621-633.
[14]	NARDELLI S C, CHE F Y, DE MONERRI N C S, et al. The histone code of Toxoplasma gondii comprises conserved and unique posttranslational modifications[J].mBio, 2013, 4(6):e00922-13.
[15]	TREECK M, SANDERS J L, ELIAS J E, et al. The phosphoproteomes of Plasmodium falciparum and Toxoplasma gondii reveal unusual adaptations within and beyond the parasites' boundaries[J].Cell Host Microbe, 2011, 10(4):410-419.
[16]	李浩瑞, 黄海斌, 杨桂连.顶复门原虫蛋白质泛素化修饰的研究进展[J].中国寄生虫学与寄生虫病杂志, 2019, 37(2):223-227.LI H R, HUANG H B, YANG G L.Advances in ubiquitination modification of apicomplexa protozoans[J].Chinese Journal of Parasitology and Parasitic Diseases, 2019, 37(2):223-227.(in Chinese)
[17]	MANDALASI M, KIM H W, THIEKER D, et al. A terminal α3-galactose modification regulates an E3 ubiquitin ligase subunit in Toxoplasma gondii[J].J Biol Chem, 2020, 295(27):9223-9243.
[18]	WANG J C, DIXON S E, TING L M, et al. Lysine acetyltransferase GCN5b Interacts with AP2 factors and is required for Toxoplasma gondii proliferation[J].PLoS Pathog, 2014, 10(1):e1003830.
[19]	BRAUN L, CANNELLA D, PINHEIRO A M, et al. The small ubiquitin-like modifier (SUMO)-conjugating system of Toxoplasma gondii[J].Int J Parasitol, 2009, 39(1):81-90.
[20]	GEISS-FRIEDLANDER R, MELCHIOR F.Concepts in sumoylation:a decade on[J].Nat Rev Mol Cell Biol, 2007, 8(12):947-956.
[21]	HAY R T.SUMO:A history of modification[J].Mol Cell, 2005, 18(1):1-12.
[22]	LINDER M E, DESCHENES R J.Palmitoylation:policing protein stability and traffic[J].Nat Rev Mol Cell Biol, 2007, 8(1):74-84.
[23]	TOM C T M B, MARTIN B R.Fat chance! Getting a grip on a slippery modification[J].ACS Chem Biol, 2013, 8(1):46-57.
[24]	FRÉNAL K, TAY C L, MUELLER C, et al. Global analysis of apicomplexan protein S-acyl transferases reveals an enzyme essential for invasion[J].Traffic, 2013, 14(8):895-911.
[25]	CHILD M A, HALL C I, BECK J R, et al. Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion[J].Nat Chem Biol, 2013, 9(10):651-656.
[26]	FOE I T, CHILD M A, MAJMUDAR J D, et al. Global analysis of palmitoylated proteins in Toxoplasma gondii[J].Cell Host Microbe, 2015, 18(4):501-511.
[27]	ALAM M M, SOLYAKOV L, BOTTRILL A R, et al. Phosphoproteomics reveals malaria parasite Protein Kinase G as a signalling hub regulating egress and invasion[J].Nat Commun, 2015, 6(1):7285.
[28]	HE C, CHEN A Y, WEI H X, et al. Phosphoproteome of Toxoplasma gondii infected host cells reveals specific cellular processes predominating in different phases of infection[J].Am J Trop Med Hyg, 2017, 97(1):236-244.
[29]	PEREZ-CERVERA Y, HARICHAUX G, SCHMIDT J, et al. Direct evidence of O-GlcNAcylation in the apicomplexan Toxoplasma gondii:a biochemical and bioinformatic study[J].Amino Acids, 2011, 40(3):847-856.
[30]	HART G W, HOUSLEY M P, SLAWSON C.Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins[J].Nature, 2007, 446(7139):1017-1022.
[31]	TOMITA T, SUGI T, YAKUBU R, et al. Making home sweet and sturdy:Toxoplasma gondii ppGalNAc-Ts glycosylate in hierarchical order and confer cyst wall rigidity[J].mBio, 2017, 8(1):e02048-16.
[32]	KHURANA S, COFFEY M J, JOHN A, et al. Protein O-fucosyltransferase 2-mediated O-glycosylation of the adhesin MIC2 is dispensable for Toxoplasma gondii tachyzoite infection[J].J Biol Chem, 2019, 294(5):1541-1553.
[33]	BANDINI G, LEON D R, HOPPE C M, et al. O-Fucosylation of thrombospondin-like repeats is required for processing of microneme protein 2 and for efficient host cell invasion by Toxoplasma gondii tachyzoites[J].J Biol Chem, 2019, 294(6):1967-1983.
[34]	ALBUQUERQUE-WENDT A, JACOT D, DOS SANTOS PACHECO N, et al. C-Mannosylation of Toxoplasma gondii proteins promotes attachment to host cells and parasite virulence[J].J Biol Chem, 2020, 295(4):1066-1076.
[35]	BANDINI G, ALBUQUERQUE-WENDT A, HEGERMANN J, et al. Protein O-and C-glycosylation pathways in Toxoplasma gondii and Plasmodium falciparum[J].Parasitology, 2019, 146(14):1755-1766.
[36]	BANDINI G, AGOP-NERSESIAN C, VAN DER WEL H, et al. The nucleocytosolic O-fucosyltransferase SPINDLY affects protein expression and virulence in Toxoplasma gondii[J].J Biol Chem, 2021, 296:100039.
[37]	TRENHOLME K, MAREK L, DUFFY S, et al. Lysine acetylation in sexual stage malaria parasites is a target for antimalarial small molecules[J].Antimicrob Agents Chemother, 2014, 58(7):3666-3678.
[38]	JEFFERS V, SULLIVAN W J.Lysine acetylation is widespread on proteins of diverse function and localization in the protozoan parasite Toxoplasma gondii[J].Eukaryot Cell, 2012, 11(6):735-742.
[39]	NAGULESWARAN A, ELIAS E V, MCCLINTICK J, et al. Toxoplasma gondii lysine acetyltransferase GCN5-A functions in the cellular response to alkaline stress and expression of cyst genes[J].PLoS Pathog, 2010, 6(12):e1001232.
[40]	JEFFERS V, GAO H Y, CHECKLEY L A, et al. Garcinol inhibits GCN5-mediated lysine acetyltransferase activity and prevents replication of the parasite Toxoplasma gondii[J].Antimicrob Agents Chemother, 2016, 60(4):2164-2170.
[41]	WANG Z A, COLE P A.The chemical biology of reversible lysine post-translational modifications[J].Cell Chem Biol, 2020, 27(8):953-969.
[42]	BOUGDOUR A, MAUBON D, BALDACCI P, et al. Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites[J].J Exp Med, 2009, 206(4):953-966.
[43]	WANG Z X, HU R S, ZHOU C X, et al. Label-free quantitative acetylome analysis reveals Toxoplasma gondii genotype-specific acetylomic signatures[J].Microorganisms, 2019, 7(11):510.
[44]	BEDFORD M T, CLARKE S G.Protein arginine methylation in mammals:who, what, and why[J].Mol Cell, 2009, 33(1):1-13.
[45]	EL BISSATI K, SUVOROVA E S, XIAO H, et al. Toxoplasma gondii arginine methyltransferase 1(PRMT1) is necessary for centrosome dynamics during tachyzoite cell division[J].mBio, 2016, 7(1):e02094-15.
[46]	LI X L, HU X, WAN Y J, et al. Systematic identification of the lysine succinylation in the protozoan parasite Toxoplasma gondii[J].J Proteome Res, 2014, 13(12):6087-6095.
[47]	ZHANG Z H, TAN M J, XIE Z Y, et al. Identification of lysine succinylation as a new post-translational modification[J].Nat Chem Biol, 2011, 7(1):58-63.
[48]	MCFADDEN G I, YEH E.The apicoplast:now you see it, now you don't[J].Int J Parasitol, 2017, 47(2-3):137-144.
[49]	ALONSO A M, TUROWSKI V R, RUIZ D M, et al. Exploring protein myristoylation in Toxoplasma gondii[J].Exp Parasitol, 2019, 203:8-18.
[50]	YANG Q Y, LI Y L, APALIYA M T, et al. The response of Rhodotorula mucilaginosa to patulin based on lysine crotonylation[J].Front Microbiol, 2018, 9:2025.
[51]	曹喜兵, 赵振利, 曹亚兵, 等. 蛋白质巴豆酰化修饰研究进展[J].河南林业科技, 2020, 40(3):25-28.CAO X B, ZHAO Z L, CAO Y B, et al. Research progress of protein crotonylation modification[J].Journal Henan for Science Technology, 2020, 40(3):25-28.(in Chinese)
[52]	尹德琦, 张越, 王大为, 等. 两种不同表型弓形虫虫株赖氨酸巴豆酰化和2-羟基异丁基酰化修饰的差异性分析[C]//中国畜牧兽医学会兽医寄生虫学分会第一届青年科学家学术论坛摘要集.武汉:中国畜牧兽医学会, 2019:1.YIN D Q, ZHANG Y, WANG D W, et al. The difference of lysine crotonylation and 2-hydroxyisobutylation between two different phenotypes of Toxoplasma gondii[C]//Abstracts of the First Academic Forum for Young Scientists of the Veterinary Parasitology Branch of the Chinese Association of Animal Husbandry and Veterinary Medicine.Wuhan:Chinese Association of Animal Husbandry and Veterinary Medicine, 2019:1.(in Chinese)
[53]	葛荟瑶.银屑病蛋白质翻译后修饰赖氨酸2-羟基异丁酰化研究[D].合肥:安徽医科大学, 2020.GE H Y.Study on post-translational modification of lysine 2-hydroxyisobutyrylation in psoriasis[D].Hefei:Anhui Medical University, 2020.(in Chinese)
[54]	NIE L B, LIANG Q L, ELSHEIKHA H M, et al. Global profiling of lysine 2-hydroxyisobutyrylome in Toxoplasma gondii using affinity purification mass spectrometry[J].Parasitol Res, 2020, 119(12):4061-4071.
[55]	XIE Z Y, DAI J B, DAI L Z, et al. Lysine succinylation and lysine malonylation in histones[J].Mol Cell Proteom, 2012, 11(5):100-107.
[56]	LIN H N, SU X Y, HE B.Protein lysine acylation and cysteine succination by intermediates of energy metabolism[J].ACS Chem Biol, 2012, 7(6):947-960.
[57]	NIE L B, LIANG Q L, DU R, et al. Global proteomic analysis of lysine malonylation in Toxoplasma gondii[J].Front Microbiol, 2020, 11:776.
[58]	FRÉNAL K, DUBREMETZ J F, LEBRUN M, et al. Gliding motility powers invasion and egress in Apicomplexa[J].Nat Rev Microbiol, 2017, 15(11):645-660.
[59]	FRENAL K, KEMP L E, SOLDATI-FAVRE D.Emerging roles for protein S-palmitoylation in Toxoplasma biology[J].Int J Parasitol, 2014, 44(2):121-131.
[60]	GILK S D, GASKINS E, WARD G E, et al. GAP45 phosphorylation controls assembly of the Toxoplasma myosin XIV complex[J].Eukaryot Cell, 2009, 8(2):190-196.
[61]	CARON C, BOYAULT C, KHOCHBIN S.Regulatory cross-talk between lysine acetylation and ubiquitination:role in the control of protein stability[J].BioEssays, 2005, 27(4):408-415.
[62]	BADODI S, BARUFFALDI F, GANASSI M, et al. Phosphorylation-dependent degradation of MEF2C contributes to regulate G2/M transition[J].Cell Cycle, 2015, 14(10):1517-1528.
[63]	WITZE E S, OLD W M, RESING K A, et al. Mapping protein post-translational modifications with mass spectrometry[J].Nat Meth, 2007, 4(10):798-806.
[64]	YAKUBU R R, NIEVES E, WEISS L M.The Methods employed in mass spectrometric analysis of posttranslational modifications (PTMs) and protein-protein interactions (PPIs)[M]//WOODS A G, DARIE C C.Advancements of Mass Spectrometry in Biomedical Research.Cham:Springer, 2019:169-198.
[65]	ROYCHOWDHURY T, CHATTOPADHYAY S.Chemical decorations of "MARs" residents in orchestrating eukaryotic gene regulation[J].Front Cell Dev Biol, 2020, 8:602994.
[66]	XUE B, JEFFERS V, SULLIVAN JR W J, et al. Protein intrinsic disorder in the acetylome of intracellular and extracellular Toxoplasma gondii[J].Mol BioSyst, 2013, 9(4):645-657.
[67]	CABALLERO M C, ALONSO A M, DENG B, et al. Identification of new palmitoylated proteins in Toxoplasma gondii[J].Biochim Biophys Acta Proteins Proteom, 2016, 1864(4):400-408.
[68]	SWANEY D L, VILLÉN J.Proteomic analysis of protein posttranslational modifications by mass spectrometry[J].Cold Spring Harb Protoc, 2016, 2016(3):pdb.top077743.
[69]	王欣悦, 张莉.蛋白质组学及蛋白质翻译后修饰在畜牧领域中的应用研究进展[J].中国畜牧兽医, 2019, 46(4):1063-1073.WANG Y L, ZHANG L.Research progress on application of proteomics and post-translational modification of proteins in animal husbandry[J].China Animal Husbandry & Veterinary Medicine, 2019, 46(4):1063-1073.(in Chinese)
[70]	AEBERSOLD R, MANN M.Mass-spectrometric exploration of proteome structure and function[J].Nature, 2016, 537(7620):347-355.
[71]	KIM M S, ZHONG J, PANDEY A.Common errors in mass spectrometry-based analysis of post-translational modifications[J].Proteomics, 2016, 16(5):700-714.
[72]	马骏骏, 王旭初, 聂小军.生物信息学在蛋白质组学研究中的应用进展[J].生物信息学, 2020, 19(2):85-91.MA J J, WANG X C, NIE X J.Advances in application of bioinformatics in proteomics research[J].Chinese Journal of Bioinformatics, 2020, 19(2):85-91.(in Chinese)
[73]	MEIER F, BRUNNER A D, FRANK M, et al. diaPASEF:parallel accumulation-serial fragmentation combined with data-independent acquisition[J].Nat Methods, 2020, 17(12):1229-1236.
[74]	NAWAZ M, MALIK I, HAMEED M, et al. Modifications of histones in parasites as drug targets[J].Vet Parasitol, 2020, 278:109029.