A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin

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.

Automated summary

The protein phosphatase PtpB from Mycobacterium tuberculosis is found to inhibit the host inflammasome-pyroptosis pathway by dephosphorylating phosphatidylinositol-4-monophosphate and phosphatidylinositol-(4,5)-bisphosphate in host cell membrane, disrupting the localization of cleaved GSDMD and inhibiting cytokine release and pyroptosis of macrophages. This phosphatase activity requires PtpB binding to ubiquitin. Disrupting phospholipid phosphatase activity or the ubiquitin-interacting motif of PtpB enhances host immune responses and reduces intracellular pathogen survival.