Abstract:The PE_PGRS33 protein is a member of the proline-glutamic_polymorphic GC-rich repeat sequence (PE_PGRS) subfamily, which is encoded by the Rv1818c gene. It is exposed on the cell wall surface in Mycobacterium tuberculosis and is expressed only in the Mycobacterium tuberculosis complex. PE_PGRS33 protein is closely associated with the pathogenicity, virulence and antigenic variation of Mycobacterium tuberculosis. Herein, to provide a reference for the study of the pathogenic mechanism of tuberculosis and the development of preventive and diagnostic strategies, we review PE_PGRS33’s structure, function, pathogenesis, gene regulation and applications in the development of vaccines and diagnostic reagents.
鞠晓红, 王月华, 方芳. 结核分枝杆菌PE_PGRS33蛋白的研究进展[J]. 中国人兽共患病学报, 2020, 36(11): 949-955.
JU Xiao-hong, WANG Yue-hua, FANG Fang. Research progress on the PE_PGRS33 protein of Mycobacterium tuberculosis. Chinese Journal of Zoonoses, 2020, 36(11): 949-955.
[1] Fishbein S, van WN, Warren RM,et al. Phylogeny to function: PE/PPE protein evolution and impact on Mycobacterium tuberculosis pathogenicity[J]. Mol Microbiol, 2015, 96(5):901-916.DOI: 10.1111/mmi.12981 [2] Deng WY, Long QX, Zeng J, et al.Mycobacterium tuberculosis PE_ PGRS41 Enhances the intracellular survival of M. smegmatis within macrophages via blocking innate immunity and inhibition of host defense[J]. Sci Rep, 2017, 7(4): 1-13.DOI:10.1038/srep46716 [3] Long QX, Xiang XH, Yin QQ, et al.PE_PGRS62 promotes the survival of Mycobacterium smegmatis within macrophages via disrupting ER stress-mediated apoptosis[J]. J Cell Physiol, 2019, 234(11): 19774-19784.DOI: 10.1002/jcp.28577 [4] Yang W, Deng W, Zeng J, et al.Mycobacterium tuberculosis PE_PGRS18 enhances the intracellular survival of M. smegmatis via altering host macrophage cytokine profiling and attenuating the cell apoptosis[J].Apoptosis,2017,22(4):502-509.DOI: 10.1007/s10495-016-1336-0 [5] Nain Z, Karim MM, Sen MK,et al.Structural basis and designing of peptide vaccine using PE-PGRS family protein of Mycobacterium ulcerans-An integrated vaccinomics approach[J].Mol Immunl, 2020,120(4):146-163.DOI: 10.1016/j.molimm.2020.02.009 [6] 陈浩天,付玉荣,伊正君.结核分枝杆菌PE_PGRS33蛋白的生物信息学分析[J].中国病原生物学,2019,14(7):780-785.DOI:10.13350/j.cjbp.190708 [7] Cascioferro A, Daleke MH, Ventura M, et al.Functional dissection of the PE domain responsible for translocation of PE_PGRS33 across the mycobacterial cell wall[J]. PLoS ONE,2011, 6(11): e27713.DOI: 10.1371/journal.pone.0027713 [8] Cadieux N, Parra M,Cohen H, et al.Induction of cell death after localization to the host cell mitochondria by the Mycobacterium tuberculosis PE_PGRS33 protein[J]. Microbiology,2011, 157(1), 793-804.DOI: 10.1099/mic.0.041996-0 [9] Daleke MH, Cascioferro A, de Punder K, et al.Conserved Pro-Glu (PE) and Pro-Pro-Glu (PPE) protein domains target LipY lipases of pathogenic mycobacteria to the cell surface via the ESX-5 pathway[J]. J Biol Chem,2011,286(21): 19024-19034.DOI: 10.1074/jbc.M110.204966 [10] Beckham, KSH,Ciccarelli L,Bunduc CM, et al.Structure of the mycobacterial ESX-5 type VII secretion system membrane complex by single particle analysis[J]. Nat Microbiol, 2017,47(2):1-8.DOI: 10.1038/nmicrobiol.2017.47 [11] Burggraaf MJ,Speer A,Meijers AS,et al.Type VII secretion substrates of pathogenic mycobacteria are processed by a surface protease[J].mBio,2019,10(5):e0951-19.DOI: 10.1128/mBio.01951-19 [12] Cohen I, Parada C, Acosta-Gio E, et al.The PGRS domain from PE_PGRS33 of Mycobacterium tuberculosis is target of humoral immune response in mice and humans[J]. Front Immunol 2014,5(3):1-9.DOI: 10.3389/fimmu.2014.00236 [13] Strong M, Sawaya MR, Wang S, et al.Toward the structural genomics of complexes: crystal structure of a PE/PPE protein complex from Mycobacterium tuberculosis[J]. Proc Natl Acad,2006,103(21): 8060-8065.DOI:10.1073/pnas.0602606103 [14] Supply P, Marceau M, Mangenot S, et al.Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis[J]. Nat.Genet,2013,45(2), 172-179.DOI: 10.1038/ng.2517 [15] De Maio F, Battah B, Palmieri V, et al.PE_PGRS3 of Mycobacterium tuberculosis is specifically expressed at low phosphate concentration, and its arginine-rich C-terminal domain mediates adhesion and persistence in host tissues when expressed in Mycobacterium smegmatis[J]. Cell Microbiol, 2018, 20(12): e12952.DOI: 10.1111/cmi.12952 [16] Vallecillo AJ, Espitia C.Expression of Mycobacterium tuberculosis pe_pgrs33 is repressed during stationary phase and stress conditions, and its transcription is mediated by sigma factor A[J].Microb Pathog, 2009, 46(1):119-127.DOI: 10.1016/j.micpath.2008.11.003 [17] Copin R., Coscolla M., Seiffffert SN,et al.Sequence diversity in the pe_pgrs genes of Mycobacterium tuberculosis is independent of human T cell recognition[J]. MBio,2014,5(1), e00960.DOI: 10.1128/mBio.00960-13 [18] Camassa S, Palucci I, Iantomasi R, et al.Impact of pe_pgrs33 gene polymorphisms on Mycobacterium tuberculosis infection and pathogenesis[J]. Front Cell Infec Microbiol,2017, 7(137):1-16. DOI: 10.3389/fcimb.2017.00137 [19] Talaricoa S, Caveb MD, Foxman B,et al.Association of Mycobacterium tuberculosis PE_PGRS33 Polymorphism with Clinical and Epidemiological Characteristics[J]. Tuberculosis (Edinb). 2007,87(4): 338-346. DOI: 10.1016/j.tube.2007.03.003 [20] Zumbo1 A, PaluccIi, Cascioferro A, et al. Functional dissection of protein domains involved in the immunomodulatory properties of PE_PGRS33 of Mycobacterium tuberculosis[J].Pathog Dis,2013,69(3):232-239.DOI: 10.1111/2049-632X.12096 [21] Palucci I, Camassa S, Cascioferro A,et al.PE PGRS33 contributes to Mycobacterium tuberculosis entry in macrophages through interaction with TLR2[J]. PLoS One 2016,11(3):e0150800.DOI: 10.1371/journal.pone.0150800 [22] Meena PR, Monu, Meena LS.Fibronectin binding protein and Ca2+ play an access key role to mediate pathogenesis Mycobacterium tuberculosis; An overview[J]. Biotechnol Appl Biochem, 2016, 63(6): 820-826.DOI: 10.1002/bab.1434 [23] Yeruva VC, Kulkarni A, Khandelwal R, et al.The PE_PGRS proteins of Mycobacterium tuberculosis are Ca2+ binding mediators of host-pathogen interaction[J]. Biochemistry,2016,55(33):4675-4687.DOI: 10.1021/acs.biochem.6b00289 [24] Grover S, Sharma T, Singh Y, et al.The PGRS domain of Mycobacterium tuberculosis PE_PGRS protein Rv0297 is involved in endoplasmic reticulum stress-mediated apoptosis through Toll-like receptor 4[J]. mBio, 2018, 9(3): e01017.DOI: 10.1128/mBio.01017-18 [25] Moreno-Altamirano MM, Paredes-Gonzalez IS, Espitia C, et al.Bioinformatic identification of Mycobacterium tuberculosis proteins likely to target host cell mitochondria: virulence factors?[J]. Microb Inform Exp,2012,2(1):1-10.DOI: 10.1186/2042-5783-2-9 [26] Aguilar-López BA, Correa F,Moreno- Altamirano MMB,et al.LprG and PE_PGRS33 Mycobacterium tuberculosis virulence factors induce differential mitochondrial dynamics in macrophages[J]. Scand J Immunol,2019,89(1):e12728.DOI: 10.1111/sji.12728 [27] West A P, Brodsky I E, Rahner C, et al.TLR signalling augments macrophage bactericidal activity through mitochondrial ROS[J]. Nature, 2011, 472(7344): 476-480.DOI: 10.1038/nature09973 [28] Ahmad J, Khubaib M,Sheikh JA,et al.Disorder-to-order transition in PE-PPE proteins of Mycobacterium tuberculosis augments the pro-pathogen immune response[J]. FEBS Open Bio,2020,10(1):70-85.DOI: 10.1002/2211-5463.12749 [29] Minerva1, Maio FD, Camassa S,et al.Evaluation of PE PGRS33 as a potential surface target for humoral responses against Mycobacterium tuberculosis[J].Pathog Dis, 2017,75(8):1-8.DOI: 10.1093/femspd/ftx100 [30] Michela Sali M, Sante GD, Cascioferro A,et al.Surface Expression of MPT64 as a fusion with the PE domain of PE_PGRS33 enhances Mycobacterium bovis BCG protective activity against Mycobacterium tuberculosis in mice[J].Infect Immun, 2010, 78(12): 5202-5213.DOI: 10.1128/IAI.00267-10