The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation
Year: 2014
Type: article
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.
DOI: 10.1084/jem.20132486
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Institutes of Health, Japan Society for the Promotion of Science, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: Colitis, Colon Cancer and the NLR Family, G1111625284, G1156522830, G1850526206, G2669406523, Confocal Microscopy Imaging System, G2859628490, G292170998, G3017212221, G3770139804, G391342467, G3963602007, G3968097173, G406480652, G4293093837, G5641079710, Negative Regulation of NLRP1-inflammasomes by the linear ubiquitin assembly compl, G6497015641, G6848630851, G6918348011, G6989976097, G727807116, G7572913590, USC Research Center for Liver Disease, G8549599477, G893857917, Molecular and Functional Analysis of Innate Immune Receptors
OpenAlex ID: W2139206194