The deubiquitinating enzyme, ubiquitin‐specific peptidase 50, regulates inflammasome activation by targeting the ASC adaptor protein

NLRP3-mediated inflammasome activation promotes caspase-1-dependent production of IL-1β and requires the adaptor protein ASC. Compared to the priming and activation mechanisms of the inflammasome signaling pathway, post-translational ubiquitination/deubiquitination mechanisms controlling inflammasome activation have not been clearly addressed. We here demonstrate that the deubiquitinating enzyme USP50 binds to the ASC protein and subsequently regulates the inflammasome signaling pathway through deubiquitinating the lysine 63-linked polyubiquitination of ASC. USP50-knockdown in human THP-1 cells and mouse bone marrow-derived macrophages shows a significant decrease in pro-caspase-1 cleavage, resulting in reduced secretion of IL-1β and IL-18 upon treatment with NLRP3 stimuli and a reduction in ASC speck formation and oligomerization. Thus, we elucidate a novel regulatory mechanism of the inflammasome signaling pathway mediated by the USP50 deubiquitinating enzyme. This article is protected by copyright. All rights reserved.