2. Academic Validation
  3. A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin

A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin

  • Science. 2022 Oct 14;378(6616):eabq0132. doi: 10.1126/science.abq0132.
Qiyao Chai # 1,  Shanshan Yu # 2,  Yanzhao Zhong # 1 3,  Zhe Lu 1 3,  Changgen Qiu 1 3,  Yang Yu 1 3,  Xinwen Zhang 1 3,  Yong Zhang 1,  Zehui Lei 1 3,  Lihua Qiang 1 3,  Bing-Xi Li 1,  Yu Pang 2,  Xiao-Bo Qiu 4 5,  Jing Wang 1,  Cui Hua Liu 1 3
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 2 Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China.
  • 3 Savaid Medical School, University of Chinese Academy of Sciences, Beijing 101408, China.
  • 4 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
  • 5 Ministry of Education Key Laboratory of Cell Proliferation and Regulation Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
  • # Contributed equally.
PMID: 36227980 DOI: 10.1126/science.abq0132
Abstract

The inflammasome-mediated cleavage of gasdermin D (GSDMD) causes Pyroptosis and inflammatory cytokine release to control pathogen Infection, but how pathogens evade this immune response remains largely unexplored. Here we identify the known protein Phosphatase PtpB from Mycobacterium tuberculosis as a phospholipid Phosphatase inhibiting the host inflammasome-pyroptosis pathway. Mechanistically, PtpB dephosphorylated phosphatidylinositol-4-monophosphate and phosphatidylinositol-(4,5)-bisphosphate in host cell membrane, thus disrupting the membrane localization of the cleaved GSDMD to inhibit cytokine release and Pyroptosis of macrophages. Notably, this Phosphatase activity requires PtpB binding to ubiquitin. Disrupting phospholipid Phosphatase activity or the ubiquitin-interacting motif of PtpB enhanced host GSDMD-dependent immune responses and reduced intracellular pathogen survival. Thus, pathogens inhibit Pyroptosis and counteract host immunity by altering host membrane composition.

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