title: The deubiquitinating enzyme, ubiquitin-specific peptidase 50, regulates inflammasome activation by targeting the ASC adaptor protein.
abstract: NOD-like receptor family protein 3 (NLRP3)-mediated inflammasome activation promotes caspase-1-dependent production of interleukin-1β (IL-1β) and requires the adaptor protein ASC. Compared with 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 by 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 procaspase-1 cleavage, resulting in a reduced secretion of IL-1β and interleukin-18 (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.
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Dongyeob
authors.initials: D
authors.lastname: Seo
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: You
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Sehee
authors.initials: S
authors.lastname: Chung
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Ji-Hyung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Su Myung
authors.initials: SM
authors.lastname: Jung
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Youn Sook
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Seok Hee
authors.initials: SH
authors.lastname: Park
mesh_terms: D000818:Animals; D055162:Biocatalysis; D001854:Bone Marrow Cells / Q000166:cytology; D053468:CARD Signaling Adaptor Proteins; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D034622:RNA Interference; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D050505:Mutant Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C402202:PYCARD protein, human; D025821:Polyubiquitin; C579214:USP50 protein, human; C000619247:USP50 protein, mouse; D064570:Ubiquitin-Specific Proteases; D008239:Lysine
keywords: ASC adaptor protein; Inflammasome; USP50 deubiquitinating enzyme