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J Exp Med. 2014 Jun 30;211(7):1333-47. doi: 10.1084/jem.20132486. Epub 2014 Jun 23.

The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation.

Author information

  • 1Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
  • 2Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
  • 3Department 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.
  • 4Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 jaeujung@med.usc.edu.

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.

© 2014 Rodgers et al.

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PMID:
24958845
[PubMed - indexed for MEDLINE]
PMCID:
PMC4076580
Free PMC Article

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