CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China.
Science. 2022 Oct 14;378(6616):eabq0132. doi: 10.1126/science.abq0132.
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 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.
炎症小体介导热休克蛋白家族成员 D（gasdermin D，GSDMD）的切割会引发细胞焦亡和炎症细胞因子释放，从而控制病原体感染，但病原体如何逃避这种免疫反应在很大程度上仍未得到探索。在这里，我们鉴定出 中的已知蛋白磷酸酶 PtpB 是一种磷脂磷酸酶，可抑制宿主炎症小体-细胞焦亡途径。在机制上，PtpB 去磷酸化了宿主细胞膜中的磷脂酰肌醇-4-单磷酸和磷脂酰肌醇-（4,5）-二磷酸，从而破坏了切割的 GSDMD 在细胞膜上的定位，抑制了巨噬细胞中细胞因子的释放和细胞焦亡。值得注意的是，这种磷酸酶活性需要 PtpB 与泛素结合。破坏磷脂磷酸酶活性或 PtpB 的泛素相互作用基序会增强宿主依赖于 GSDMD 的免疫反应，并减少细胞内病原体的存活。因此，病原体通过改变宿主膜组成来抑制细胞焦亡和拮抗宿主免疫。
