代谢调控蛋白A调控革兰阳性菌代谢与毒力偶联的研究进展

doi:10.3969/j.issn.1674-8115.2021.04.020

摘要/Abstract

摘要：

代谢调控蛋白A（catabolite control protein A，CcpA）是革兰阳性菌重要的多效调节因子，在磷酸烯醇丙酮酸依赖的磷酸转移酶系统辅助下，能与靶基因上的特异性DNA序列——代谢反应元件结合，促进或阻遏靶基因表达，从而调控细菌的生理过程和毒力。CcpA通过介导微生物碳分解代谢物阻遏效应，控制细菌摄取与利用外界环境中营养物质，保障其高效利用能源。CcpA通过直接或间接调控细菌的代谢过程和毒力基因表达，将细菌的代谢与毒力偶联。该文介绍了CcpA的作用机制及其对细菌多种代谢途径和致病性调控的研究进展。

关键词: 代谢调控蛋白A（CcpA）, 碳分解代谢物阻遏效应（CCR）, 代谢, 毒力

Abstract:

Catabolite control protein A (CcpA) is an important pleiotropic regulator in Gram-positive bacteria. With the assistance of the phosphoenolpyruvate-dependent carbohydrate phosphotransferase system, CcpA undergoes a conformational change and interacts with catabolite responsive element, a specific DNA sequence on the target gene, activating or repressing expression of the target gene, thereby controlling the physiological processes and virulence of bacteria. CcpA mediates the carbon catabolite repression effect of microorganisms to control the uptake and utilization of environmental nutrients, ensuring the efficient use of energy by bacteria. CcpA regulates bacterial metabolism and virulence gene expression directly or indirectly, coupling the metabolism and virulence of bacteria. This review describes the mechanism of CcpA function, and summarizes the research progress of CcpA in regulating multiple metabolic pathways and pathogenicity of bacteria.

Key words: catabolite control protein A (CcpA), carbon catabolite repression (CCR), metabolism, virulence

中图分类号:

R378

杨紫瑜, 秦娟秀, 李敏, 刘倩. 代谢调控蛋白A调控革兰阳性菌代谢与毒力偶联的研究进展[J]. 上海交通大学学报(医学版), 2021, 41(4): 535-539.

Zi-yu YANG, Juan-xiu QIN, Min LI, Qian LIU. Progress of catabolite control protein A in the regulation of metabolism and virulence of Gram-positive bacteria[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(4): 535-539.

图/表 1

参考文献 44

1	Henkin TM, Grundy FJ, Nicholson WL, et al. Catabolite repression of α amylase gene expression in Bacillus subtilis involves a trans-acting gene product homologous to the Escherichia colilacl and galR repressors[J]. Mol Microbiol, 1991, 5(3): 575-584.
2	Brückner R, Titgemeyer F. Carbon catabolite repression in bacteria: choice of the carbon source and autoregulatory limitation of sugar utilization[J]. FEMS Microbiol Lett, 2002, 209(2): 141-148.
3	Park H, McGill SL, Arnold AD, et al. Pseudomonad reverse carbon catabolite repression, interspecies metabolite exchange, and consortial division of labor[J]. Cell Mol Life Sci, 2020, 77(3): 395-413.
4	Grand M, Aubourg M, Pikis A, et al. Characterization of the Gen locus involved in β-1,6-oligosaccharide utilization by Enterococcus faecalis[J]. Mol Microbiol, 2019, 112(6): 1744-1756.
5	Warner JB, Lolkema JS. CcpA-dependent carbon catabolite repression in bacteria[J]. Microbiol Mol Biol Rev, 2003, 67(4): 475-490.
6	Yang Y, Zhang L, Huang H, et al. A flexible binding site architecture provides new insights into CcpA global regulation in Gram-positive bacteria[J]. mBio, 2017, 8(1): e02004-16.
7	Galinier A, Haiech J, Kilhoffer MC, et al. The Bacillus subtiliscrh gene encodes a HPr-like protein involved in carbon catabolite repression[J]. Proc Natl Acad Sci USA, 1997, 94(16): 8439-8444.
8	Schumacher MA, Seidel G, Hillen W, et al. Phosphoprotein Crh-Ser46-P displays altered binding to CcpA to effect carbon catabolite regulation[J]. J Biol Chem, 2006, 281(10): 6793-6800.
9	Schumacher MA, Seidel G, Hillen W, et al. Structural mechanism for the fine-tuning of CcpA function by the small molecule effectors glucose 6-phosphate and fructose 1,6-bisphosphate[J]. J Mol Biol, 2007, 368(4): 1042-1050.
10	Schumacher MA, Sprehe M, Bartholomae M, et al. Structures of carbon catabolite protein A-(HPr-Ser46-P) bound to diverse catabolite response element sites reveal the basis for high-affinity binding to degenerate DNA operators[J]. Nucleic Acids Res, 2011, 39(7): 2931-2942.
11	Antunes A, Camiade E, Monot M, et al. Global transcriptional control by glucose and carbon regulator CcpA in Clostridium difficile[J]. Nucleic Acids Res, 2012, 40(21): 10701-10718.
12	Martin-Verstraete I, Stülke J, Klier A, et al. Two different mechanisms mediate catabolite repression of the Bacillus subtilis levanase operon[J]. J Bacteriol, 1995, 177(23): 6919-6927.
13	Mahr K, Hillen W, Titgemeyer F. Carbon catabolite repression in Lactobacillus pentosus: analysis of the ccpA region[J]. Appl Environ Microbiol, 2000, 66(1): 277-283.
14	Egeter O, Brückner R. Catabolite repression mediated by the catabolite control protein CcpA in Staphylococcus xylosus[J]. Mol Microbiol, 1996, 21(4): 739-749.
15	Zhang L, Liu YQ, Yang YP, et al. A novel dual-cre motif enables two-way autoregulation of CcpA in Clostridium acetobutylicum[J]. Appl Environ Microbiol, 2018, 84(8): e00114-18.
16	Al-Bayati FAY, Kahya HFH, Damianou A, et al. Pneumococcal galactose catabolism is controlled by multiple regulators acting on pyruvate formate lyase[J]. Sci Rep, 2017, 7: 43587.
17	Leiba J, Hartmann T, Cluzel ME, et al. A novel mode of regulation of the Staphylococcus aureus catabolite control protein A (CcpA) mediated by Stk1 protein phosphorylation[J]. J Biol Chem, 2012, 287(52): 43607-43619.
18	Peng Q, Zhao X, Wen J, et al. Transcription in the acetoin catabolic pathway is regulated by AcoR and CcpA in Bacillus thuringiensis[J]. Microbiol Res, 2020, 235: 126438.
19	Tobisch S, Zühlke D, Bernhardt J, et al. Role of CcpA in regulation of the central pathways of carbon catabolism in Bacillus subtilis[J]. J Bacteriol, 1999, 181(22): 6996-7004.
20	Ludwig H, Rebhan N, Blencke HM, et al. Control of the glycolytic gapA operon by the catabolite control protein A in Bacillus subtilis: a novel mechanism of CcpA-mediated regulation[J]. Mol Microbiol, 2002, 45(2): 543-553.
21	Zhang GF, Liu LB, Li C. Effects of ccpA gene deficiency in Lactobacillus delbrueckii subsp. bulgaricus under aerobic conditions as assessed by proteomic analysis[J]. Microb Cell Fact, 2020, 19: 9.
22	Li C, Sun JW, Zhang GF, et al. Effect of the absence of the CcpA gene on growth, metabolic production, and stress tolerance in Lactobacillus delbrueckii ssp. bulgaricus[J]. J Dairy Sci, 2016, 99(1): 104-111.
23	Luesink EJ, van Herpen RE, Grossiord BP, et al. Transcriptional activation of the glycolytic Las operon and catabolite repression of the gal operon in Lactococcus lactis are mediated by the catabolite control protein CcpA[J]. Mol Microbiol, 1998, 30(4): 789-798.
24	Kim JN, Burne RA. CcpA and CodY coordinate acetate metabolism in Streptococcus mutans[J]. Appl Environ Microbiol, 2017, 83(7): e03274-16.
25	Shivers RP, Dineen SS, Sonenshein AL. Positive regulation of Bacillus subtilisackA by CodY and CcpA: establishing a potential hierarchy in carbon flow[J]. Mol Microbiol, 2006, 62(3): 811-822.
26	Seidl K, Müller S, François P, et al. Effect of a glucose impulse on the CcpA regulon in Staphylococcus aureus[J]. BMC Microbiol, 2009, 9: 95.
27	Reed JM, Olson S, Brees DF, et al. Coordinated regulation of transcription by CcpA and the Staphylococcus aureus two-component system HptRS[J]. PLoS One, 2018, 13(12): e0207161.
28	Fletcher JR, Erwin S, Lanzas C, et al. Shifts in the gut metabolome and Clostridium difficile transcriptome throughout colonization and infection in a mouse model[J]. mSphere, 2018, 3(2): e00089-18.
29	Nuxoll AS, Halouska SM, Sadykov MR, et al. CcpA regulates arginine biosynthesis in Staphylococcus aureus through repression of proline catabolism[J]. PLoS Pathog, 2012, 8(11): e1003033.
30	Halsey CR, Lei SL, Wax JK, et al. Amino acid catabolism in Staphylococcus aureus and the function of carbon catabolite repression[J]. mBio, 2017, 8(1): e01434-16.
31	Faustoferri RC, Hubbard CJ, Santiago B, et al. Regulation of fatty acid biosynthesis by the global regulator CcpA and the local regulator FabT in Streptococcus mutans[J]. Mol Oral Microbiol, 2015, 30(2): 128-146.
32	Willenborg J, Fulde M, de Greeff A, et al. Role of glucose and CcpA in capsule expression and virulence of Streptococcus suis[J]. Microbiology, 2011, 157(6): 1823-1833.
33	瞿慧萍. CcpA在单核细胞增生李斯特菌中的功能初探[D]. 武汉: 华中师范大学, 2014.
34	Chen YM, Chiang YC, Tseng TY, et al. Molecular and functional analysis of the type Ⅳ pilus gene cluster in Streptococcus sanguinis SK36[J]. Appl Environ Microbiol, 2019, 85(6): e02788-18.
35	Antunes A, Martin-Verstraete I, Dupuy B. CcpA-mediated repression of Clostridium difficile toxin gene expression[J]. Mol Microbiol, 2011, 79(4): 882-899.
36	Bauer R, Mauerer S, Spellerberg B. Regulation of the β-hemolysin gene cluster of Streptococcus anginosus by CcpA[J]. Sci Rep, 2018, 8: 9028.
37	Kinkel TL, McIver KS. CcpA-mediated repression of streptolysin S expression and virulence in the group A Streptococcus[J]. Infect Immun, 2008, 76(8): 3451-3463.
38	Bischoff M, Wonnenberg B, Nippe N, et al. CcpA affects infectivity of Staphylococcus aureus in a hyperglycemic environment[J]. Front Cell Infect Microbiol, 2017, 7: 172.
39	Li J, Freedman JC, McClane BA. NanI sialidase, CcpA, and CodY work together to regulate epsilon toxin production by Clostridium perfringens type D strain CN3718[J]. J Bacteriol, 2015, 197(20): 3339-3353.
40	Martin-Verstraete I, Peltier J, Dupuy B. The regulatory networks that control Clostridium difficile toxin synthesis[J]. Toxins (Basel), 2016, 8(5): 153.
41	Varga J, Stirewalt VL, Melville SB. The CcpA protein is necessary for efficient sporulation and enterotoxin gene (cpe) regulation in Clostridium perfringens[J]. J Bacteriol, 2004, 186(16): 5221-5229.
42	Paluscio E, Watson ME, Caparon MG. CcpA coordinates growth/damage balance for Streptococcus pyogenes pathogenesis[J]. Sci Rep, 2018, 8(1): 14254.
43	Somarajan SR, Roh JH, Singh KV, et al. CcpA is important for growth and virulence of Enterococcus faecium[J]. Infect Immun, 2014, 82(9): 3580-3587.
44	Motib AS, Al-Bayati FAY, Manzoor I, et al. TprA/PhrA quorum sensing system has a major effect on pneumococcal survival in respiratory tract and blood, and its activity is controlled by CcpA and GlnR[J]. Front Cell Infect Microbiol, 2019, 9: 326.

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