Journal Club

A bacterial phospholipid phosphatase inhibits hostpyroptosis by hijacking ubiquitin

Science378, 153 (2022)

The inflammasome-mediated cleavage of gasdermin D (GSDMD) causes pyroptosis and inflammatory cytokinerelease to control pathogen infection, but how pathogens evade this immune response remains largelyunexplored. Here we identify the known protein phosphatase PtpB fromMycobacterium tuberculosisas aphospholipid phosphatase inhibiting the host inflammasome-pyroptosis pathway. Mechanistically, PtpBdephosphorylated phosphatidylinositol-4-monophosphate and phosphatidylinositol-(4,5)-bisphosphatein host cell membrane, thus disrupting the membrane localization of the cleaved GSDMD to inhibit cytokinerelease and pyroptosis of macrophages. Notably, this phosphatase activity requires PtpB binding toubiquitin. Disrupting phospholipid phosphatase activity or the ubiquitin-interacting motif of PtpBenhanced host GSDMD-dependent immune responses and reduced intracellular pathogen survival. Thus,pathogens inhibit pyroptosis and counteract host immunity by altering host membrane composition.