ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination

摘要

Deubiquitination of 3 has been suggested to contribute to inflammasome activation, but the roles and molecular mechanisms are still unclear. We here demonstrate that 1, a subunit of the deubiquitinase complex, is necessary for optimal 3‐ complex formation, oligomerization, caspase‐1 activation, and ‐1β and ‐18 production upon treatment with 3 ligands after the priming step, indicating that efficient 3 activation requires 1. Moreover, we report that 1 deficiency results in a remarkable attenuation in the syndrome severity of 3‐associated inflammatory diseases, including ‐ and Alum‐induced peritonitis and ‐induced sepsis in mice. Mechanistic studies reveal that priming induces 1 binding to 3 in an S194 phosphorylation‐dependent manner, subsequently recruiting the to remove K63‐linked ubiquitin chains of 3 upon stimulation with activators. Furthermore, deficiency of 3, the catalytically active component of , displays similar phenotypes to 1 knockout mice. Our findings reveal an 1‐mediated regulatory signaling system that controls activation of the 3 inflammasome and provide novel potential targets for treating 3‐associated inflammatory diseases.