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The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation
Open accessAbstract
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.
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“For instance, the LUBAC is reportedly essential for NLRP3 inflammasome activation27 and thus acts as a key innate immune regulator28.”
From New insights into the genetic etiology of Alzheimer’s disease and related dementias (2022) · cites this paper as [27]
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Metadata
- Authors
- Rodgers, M. A., Bowman, J. W., Fujita, H., Orazio, N., Shi, M., Liang, Q., Amatya, R., Kelly, T. J., Iwai, K., Ting, J., & Jung, J. U.
- Affiliations
- University of Southern California (US)
- Kyoto University (JP)
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan 2
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Jung, Jae U.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2014-06-23
- Volume
- 211
- Issue
- 7
- Pages
- 1333-1347
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC4076580
- OpenAlex
- W2139206194
- Cited by
- 247
- References
- 62
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 14 · 2023: 20 · 2022: 17 · 2021: 23 · 2020: 18 · 2019: 22 · 2018: 22 · 2017: 29 · 2016: 31 · 2015: 27 · 2014: 4
- FWCI
- 12.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (1s10rr022508-01a1, 1f32ai096698-01)
- Japan Society for the Promotion of Science (24112002)
- National Heart, Lung, and Blood Institute (HL110609, R01HL110609)
- National Cancer Institute (R01CA156330, CA180779, CA082057, P01CA180779, CA-31363, R01CA082057, CA115284, CA156330, R01CA031363, R01CA115284)
- National Institute of Allergy and Infectious Diseases (AI073099, 1F32AI096698, R01AI073099, R37AI029564, F32-AI096698, U19AI083025, R56AI029564, AI083025, AI029564, R01AI029564)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK048522)
- National Center for Research Resources (S10-RR022508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- LUBAC, linear ubiquitination, NLRP3 inflammasome, ASC, HOIL-1L, macrophages, IL-1β secretion, innate immunity, post-translational modification
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Carrier Proteins, Humans, Immunity, Innate, Lipopolysaccharides, Macrophages, NF-kappa B, Common Variable Immunodeficiency, Mice, Knockout, GTPase-Activating Proteins, Ubiquitin-Protein Ligases, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Mice, Interleukin-1beta, Ubiquitination, Inflammasomes
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