2. Academic Validation
  3. Pathogenic phosphorylation of linear ubiquitin machinery causes inflammasome sensor degradation

Pathogenic phosphorylation of linear ubiquitin machinery causes inflammasome sensor degradation

  • Cell Rep. 2025 Sep 23;44(9):116286. doi: 10.1016/j.celrep.2025.116286.
Yang Yu 1,  Shanshan Yu 2,  Zhe Lu 1,  Lihua Qiang 3,  Yanzhao Zhong 1,  Pupu Ge 4,  Zehui Lei 1,  Changgen Qiu 1,  Yingxu Fang 1,  Xinwen Zhang 1,  Bingxi Li 4,  Yu Pang 2,  Jing Wang 4,  Lingqiang Zhang 5,  Cui Hua Liu 6,  Qiyao Chai 7
Affiliations

Affiliations

  • 1 Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Medical School, University of Chinese Academy of Sciences, Beijing 101408, China.
  • 2 Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China.
  • 3 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China.
  • 4 Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China. Electronic address: zhanglq@nic.bmi.ac.cn.
  • 6 Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Medical School, University of Chinese Academy of Sciences, Beijing 101408, China. Electronic address: liucuihua@im.ac.cn.
  • 7 Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: chaiqy@im.ac.cn.
PMID: 40944911 DOI: 10.1016/j.celrep.2025.116286
Abstract

Host immune cells are equipped with cytosolic sensors to detect invading pathogens and initiate anti-infectious responses. However, how pathogens undermine host intracellular surveillance for persistent Infection is not fully understood. Here, we identify that Mycobacterium tuberculosis protein kinase PknG subverts inflammasome sensor NLRP3-mediated cytokine release and Pyroptosis by targeting host linear ubiquitin chain assembly complex (LUBAC). Mechanistically, PknG phosphorylates the LUBAC subunit HOIL-1L to prevent it from engaging in LUBAC formation, thereby suppressing linear ubiquitination of inflammasome adaptor ASC to dampen NLRP3 inflammasome assembly. Meanwhile, this phosphorylation stabilizes and activates HOIL-1L, which, in turn, exerts ubiquitin Ligase activity to mediate K48-linked ubiquitination of NLRP3 for degradation. Disrupting the kinase activity or HOIL-1L-interacting region of PknG facilitates host NLRP3-dependent anti-Mtb immunity in mice. Thus, the Bacterial kinase disrupts host linear ubiquitin machinery and coopts its ubiquitin Ligase subunit to constitute an inter-species enzymatic cascade that drives inflammasome sensor degradation for counteracting immune surveillance.

Keywords

CP: Molecular biology; Mycobacterium tuberculosis; inflammasome; intracellular immune surveillance; linear ubiquitin chain assembly complex, LUBAC; protein kinase G, PknG; ubiquitination.

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