title: Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity.
abstract: NLRP3 is an important pattern recognition receptor involved in mediating inflammasome activation in response to viral and bacterial infections as well as various proinflammatory stimuli associated with tissue damage or malfunction. Upon activation, NLRP3 assembles a multimeric inflammasome complex comprising the adaptor ASC and the effector pro-caspase-1 to mediate the activation of caspase-1. Although NLRP3 expression is induced by the NF-κB pathway, the posttranscriptional molecular mechanism controlling the activation of NLRP3 remains elusive. Using both pharmacological and molecular approaches, we show that the activation of NLRP3 inflammasome is regulated by a deubiquitination mechanism. We further identify the deubiquitinating enzyme, BRCC3, as a critical regulator of NLRP3 activity by promoting its deubiquitination and characterizing NLRP3 as a substrate for the cytosolic BRCC3-containing BRISC complex. Our results elucidate a regulatory mechanism involving BRCC3-dependent NLRP3 regulation and highlight NLRP3 ubiquitination as a potential therapeutic target for inflammatory diseases.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bénédicte F
authors.initials: BF
authors.lastname: Py
authors.forename: Mi-Sung
authors.initials: MS
authors.lastname: Kim
authors.forename: Helin
authors.initials: H
authors.lastname: Vakifahmetoglu-Norberg
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D000072017:Deubiquitinating Enzymes; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010449:Peptide Mapping; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011714:Pyrans / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C540769:4H-thiopyran-4-one tetrahydro-3,5-bis-((4-nitrophenyl)methylene)-1,1-dioxide; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011714:Pyrans; D034741:RNA, Small Interfering; D013438:Sulfhydryl Compounds; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D010450:Endopeptidases; C579125:BRCC3 protein, mouse; D000072017:Deubiquitinating Enzymes; D020170:Caspase 1