CCDC50 suppresses NLRP3 inflammasome activity by mediating autophagic degradation of NLRP3. (28th March 2022)

• Record Type: Journal Article
• Authors: Lin, Yuxin; Li, Zibo; Wang, Yicheng; Tian, Tian; Jia, Penghui; Ye, Yu; He, Miao; Yang, Zixiao; Li, Chunmei; Guo, Deyin; Hou, Panpan
• Is Part Of: EMBO reports. Volume 23:Number 5(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-03-28
• Subjects: autophagy receptor -- CCDC50 -- IL‐1β -- inflammatory diseases -- NLRP3 inflammasome; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202154453
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: The NLRP3‐directed inflammasome complex is crucial for the host to resist microbial infection and monitor cellular damage. However, the hyperactivation of NLRP3 inflammasome is implicated in pathogenesis of inflammatory diseases, including inflammatory bowel disease (IBD). Autophagy and autophagy‐related genes are closely linked to NLRP3‐mediated inflammation in these inflammatory disorders. Here, we report that CCDC50, a novel autophagy cargo receptor, negatively regulates NLRP3 inflammasome assembly and suppresses the cleavage of pro‐caspase‐1 and interleukin 1β (IL‐1β) release by delivering NLRP3 for autophagic degradation. Transcriptome analysis showed that knockdown of CCDC50 results in upregulation of signaling pathways associated with autoinflammatory diseases. CCDC50 deficiency leads to enhanced proinflammatory cytokine response triggered by a wide range of endogenous and exogenous NLRP3 stimuli. Ccdc50 ‐deficient mice are more susceptible to dextran sulfate (DSS)‐induced colitis and exhibit more severe gut inflammation with elevated NLRP3 inflammasome activity. These results illustrate the physiological significance of CCDC50 in the pathogenicity of inflammatory diseases, suggesting protective roles of CCDC50 in keeping gut inflammation under control. Synopsis: CCDC50 suppresses NLRP3 inflammasome activity by targeting K63‐polyubiquitinated NLRP3 for selective autophagic degradation. CCDC50 functions as a guardian for host immune homeostasis through regulating NLRP3 inflammasome activity. CCDC50 delivers K63‐polyubiquitinated NLRP3 for selective autophagic degradation. CCDC50 negatively regulates NLRP3 inflammasome assembly. CCDC50 deficiency leads to enhanced proinflammatory cytokine responses. Cdc50‐deficient mice are more susceptible to DSS‐induced colitis and exhibit more severe gut inflammation. Abstract : CCDC50 suppresses NLRP3 inflammasome activity by targeting K63‐polyubiquitinated NLRP3 for selective autophagic degradation. CCDC50 functions as a guardian for host immune homeostasis through regulating NLRP3 inflammasome activity.