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  3. Microbiota-derived succinate promotes enterohaemorrhagic Escherichia coli virulence via lysine succinylation

Microbiota-derived succinate promotes enterohaemorrhagic Escherichia coli virulence via lysine succinylation

  • Nat Microbiol. 2025 Mar;10(3):749-764. doi: 10.1038/s41564-025-01931-x.
Linxing Li # 1 2 3,  Yutao Liu # 1,  Dan Liu # 1,  Jing Wang # 1,  Min Wang # 1,  Binbin Xiang 1,  Jingliang Qin 1,  Ting Yao 1,  Wanwu Li 1,  Pan Wu 1,  Qian Wang 1,  Jianji Zhang 4,  Yanli Xu 1,  Miaomiao Liu 1,  Yanling Wang 1,  Guozhen Ma 1,  Ruiying Liu 1,  Xiaoya Li 1,  Zimeng Huai 1,  Yu Huang 1,  Han Guo 1,  Bin Yang 1,  Lu Feng 1 2 3,  Di Huang 5 6 7,  Kai Zhang 8,  Lei Wang 9 10 11,  Bin Liu 12 13 14
Affiliations

Affiliations

  • 1 National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, P. R. China.
  • 2 Key Laboratory of Molecular Microbiology and Technology, Nankai University, Ministry of Education, Tianjin, P. R. China.
  • 3 Nankai International Advanced Research Institute, Shenzhen, P. R. China.
  • 4 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 5 National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, P. R. China. huangdi@nankai.edu.cn.
  • 6 Key Laboratory of Molecular Microbiology and Technology, Nankai University, Ministry of Education, Tianjin, P. R. China. huangdi@nankai.edu.cn.
  • 7 Nankai International Advanced Research Institute, Shenzhen, P. R. China. huangdi@nankai.edu.cn.
  • 8 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. kzhang@tmu.edu.cn.
  • 9 National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, P. R. China. wanglei@nankai.edu.cn.
  • 10 Key Laboratory of Molecular Microbiology and Technology, Nankai University, Ministry of Education, Tianjin, P. R. China. wanglei@nankai.edu.cn.
  • 11 Nankai International Advanced Research Institute, Shenzhen, P. R. China. wanglei@nankai.edu.cn.
  • 12 National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, P. R. China. liubin1981@nankai.edu.cn.
  • 13 Key Laboratory of Molecular Microbiology and Technology, Nankai University, Ministry of Education, Tianjin, P. R. China. liubin1981@nankai.edu.cn.
  • 14 Nankai International Advanced Research Institute, Shenzhen, P. R. China. liubin1981@nankai.edu.cn.
  • # Contributed equally.
PMID: 39891012 DOI: 10.1038/s41564-025-01931-x
Abstract

Succinate upregulates enterohaemorrhagic Escherichia coli (EHEC) virulence. Lysine succinylation, a post-translational modification, regulates cellular function in eukaryotes but is less characterized in bacteria. We hypothesized that lysine succinylation regulates EHEC virulence. Here we used SILAC-based proteomics and characterized the EHEC succinylome to show that the transcription factor, PurR, is succinylated at K24 and K55. Succinylation of PurR inhibited its ability to directly bind DNA and repress expression of a major virulence factor, the Type 3 Secretion System (T3SS), thus increasing T3SS expression. Deletion of purR, or K24E or K55E mutation, increased EHEC adherence to cells and colonization of infant rabbits. Using mice treated with streptomycin to deplete succinate, or colonized with succinate-producing Prevotella copri to increase succinate levels, we showed that microbiota-derived succinate increased succinylation of PurR to promote virulence of Citrobacter rodentium, a model for EHEC, in mice. Lastly, we identified CitC as the succinyltransferase required for PurR modification.

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