{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:34:30Z","timestamp":1791203670425,"version":"4.2.0"},"reference-count":61,"publisher":"Rockefeller University Press","issue":"7","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,6,30]]},"abstract":"<jats:p>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-\u03baB\u2013mediated 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\u2013derived macrophages (BMDMs) independently of NF-\u03baB 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\u2212\/\u2212 mice have reduced IL-1\u03b2 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.<\/jats:p>","DOI":"10.1084\/jem.20132486","type":"journal-article","created":{"date-parts":[[2014,6,24]],"date-time":"2014-06-24T03:24:47Z","timestamp":1403580287000},"page":"1333-1347","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":242,"title":["The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation"],"prefix":"10.1084","volume":"211","author":[{"given":"Mary A.","family":"Rodgers","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Bowman","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Orazio","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mude","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiming","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rina","family":"Amatya","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Iwai","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Ting","sequence":"additional","affiliation":[{"name":"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 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae U.","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2014,6,23]]},"reference":[{"key":"2023072602220198600_bib1","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.1038\/ni.2457","article-title":"Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency","volume":"13","author":"Boisson","year":"2012","journal-title":"Nat. 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