title: The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation.
abstract: Linear ubiquitination is a newly discovered posttranslational modification that is currently restricted to a small number of known protein substrates. The linear ubiquitination assembly complex (LUBAC), consisting of HOIL-1L, HOIP, and Sharpin, has been reported to activate NF-κB-mediated transcription in response to receptor signaling by ligating linear ubiquitin chains to Nemo and Rip1. Despite recent advances, the detailed roles of LUBAC in immune cells remain elusive. We demonstrate a novel HOIL-1L function as an essential regulator of the activation of the NLRP3/ASC inflammasome in primary bone marrow-derived macrophages (BMDMs) independently of NF-κB activation. Mechanistically, HOIL-1L is required for assembly of the NLRP3/ASC inflammasome and the linear ubiquitination of ASC, which we identify as a novel LUBAC substrate. Consequently, we find that HOIL-1L(-/-) mice have reduced IL-1β secretion in response to in vivo NLRP3 stimulation and survive lethal challenge with LPS. Together, these data demonstrate that linear ubiquitination is required for NLRP3 inflammasome activation, defining the molecular events of NLRP3 inflammasome activation and expanding the role of LUBAC as an innate immune regulator. Furthermore, our observation is clinically relevant because patients lacking HOIL-1L expression suffer from pyogenic bacterial immunodeficiency, providing a potential new therapeutic target for enhancing inflammation in immunodeficient patients.
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
authors: Mary A
authors: MA
authors: Rodgers
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
authors: James W
authors: JW
authors: Bowman
authors: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Hiroaki
authors: H
authors: Fujita
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
authors: Nicole
authors: N
authors: Orazio
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
authors: Mude
authors: M
authors: Shi
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
authors: Qiming
authors: Q
authors: Liang
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
authors: Rina
authors: R
authors: Amatya
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
authors: Thomas J
authors: TJ
authors: Kelly
authors: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Kazuhiro
authors: K
authors: Iwai
authors: Department of Microbiology-Immunology, Lineberger Comprehensive Cancer Center, Center for Translational Immunology and Institute for Inflammatory Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors: Jenny
authors: J
authors: Ting
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 jaeujung@med.usc.edu.
authors: Jae U
authors: JU
authors: Jung
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000276:immunology; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D046912:Multiprotein Complexes; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; C587672:IL1B protein, mouse; C514981:NEMO protein, mouse; C492716:Nlrp3 protein, mouse; C490620:Ralbp1 protein, mouse; C554944:Sipl1 protein, mouse; C492590:Rnf31 protein, mouse; C000607389:Rbck1 protein, mouse