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Phosphoenolpyruvate carboxykinase (PEPCK), encoded by pckA, is a key enzyme at the metabolic junction between the pyruvate cycle and the TCA cycle, but its role in virulence regulation remains largely unexplored. In this study, we generated a pckA deletion mutant, \u0394pckA, in Edwardsiella tarda and investigated its impact on virulence, metabolism, and vaccine potential. The \u0394pckA mutant exhibited increased antibiotic sensitivity, faster growth, reduced autoaggregation, and significantly attenuated virulence in a tilapia infection model. Quantitative proteomics revealed global downregulation of type III and type VI secretion systems (T3SS and T6SS) and upregulation of flagellar proteins. Mechanistically, accumulation of oxaloacetate (OAA) in the mutant suppressed T3SS\/T6SS expression without affecting flagellar motility. Importantly, \u0394pckA induced a robust immune response in zebrafish and conferred strong protection against lethal challenge, with relative percent survival values of 64% and 81.82% in zebrafish and tilapia, respectively. Taken together, our findings identify PEPCK as a critical metabolic regulator of E. tarda virulence and highlight \u0394pckA as a promising live attenuated vaccine candidate.<\/jats:p>","DOI":"10.3390\/biology15161338","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T11:44:53Z","timestamp":1786103093000},"page":"1338","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phosphoenolpyruvate Carboxykinase Controls Edwardsiella tarda Virulence via Oxaloacetate"],"prefix":"10.3390","volume":"15","author":[{"given":"Jiayao","family":"Wu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China"},{"name":"Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feirong","family":"Yuan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilong","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China"},{"name":"Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sihui","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China"},{"name":"Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianshun","family":"Kou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China"},{"name":"Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanwei","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China"},{"name":"Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5698-6097","authenticated-orcid":false,"given":"Bo","family":"Peng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China"},{"name":"Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jordana-Lluch, E., Barcelo, I.M., Escobar-Salom, M., Estevez, M.A., Zamorano, L., Gomez-Zorrilla, S., Sendra, E., Oliver, A., and Juan, C. 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