期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 211, 期 7, 页码 1331-1345出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20132486
关键词
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资金
- National Institutes of Health [P30 DK048522, S10 RR022508]
- GRL
- Hastings Foundation
- Fletcher Jones Foundation
- [1F32AI096698]
- [CA180779]
- [CA082057]
- [CA31363]
- [CA115284]
- [AI073099]
- [AI083025]
- [HL110609]
- [CA156330]
- [AI029564]
- Grants-in-Aid for Scientific Research [24112002, 24112001] Funding Source: KAKEN
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-kappa B-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-kappa B 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-1 beta 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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