PMID- 24958845
OWN - NLM
STAT- MEDLINE
DCOM- 20140904
LR  - 20211021
IS  - 1540-9538 (Electronic)
IS  - 0022-1007 (Print)
IS  - 0022-1007 (Linking)
VI  - 211
IP  - 7
DP  - 2014 Jun 30
TI  - The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome 
      activation.
PG  - 1333-47
LID - 10.1084/jem.20132486 [doi]
AB  - 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-kappaB-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-kappaB 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-1beta 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.
CI  - (c) 2014 Rodgers et al.
FAU - Rodgers, Mary A
AU  - Rodgers MA
AD  - Department of Molecular Microbiology and Immunology, Keck School of Medicine, 
      University of Southern California, Los Angeles, CA 90033.
FAU - Bowman, James W
AU  - Bowman JW
AD  - Department of Molecular Microbiology and Immunology, Keck School of Medicine, 
      University of Southern California, Los Angeles, CA 90033.
FAU - Fujita, Hiroaki
AU  - Fujita H
AD  - Department of Molecular and Cellular Physiology, Graduate School of Medicine, 
      Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
FAU - Orazio, Nicole
AU  - Orazio N
AD  - Department of Molecular Microbiology and Immunology, Keck School of Medicine, 
      University of Southern California, Los Angeles, CA 90033.
FAU - Shi, Mude
AU  - Shi M
AD  - Department of Molecular Microbiology and Immunology, Keck School of Medicine, 
      University of Southern California, Los Angeles, CA 90033.
FAU - Liang, Qiming
AU  - Liang Q
AD  - Department of Molecular Microbiology and Immunology, Keck School of Medicine, 
      University of Southern California, Los Angeles, CA 90033.
FAU - Amatya, Rina
AU  - Amatya R
AD  - Department of Molecular Microbiology and Immunology, Keck School of Medicine, 
      University of Southern California, Los Angeles, CA 90033.
FAU - Kelly, Thomas J
AU  - Kelly TJ
AD  - Department of Molecular Microbiology and Immunology, Keck School of Medicine, 
      University of Southern California, Los Angeles, CA 90033.
FAU - Iwai, Kazuhiro
AU  - Iwai K
AD  - Department of Molecular and Cellular Physiology, Graduate School of Medicine, 
      Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
FAU - Ting, Jenny
AU  - Ting J
AD  - 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.
FAU - Jung, Jae U
AU  - Jung JU
AD  - Department of Molecular Microbiology and Immunology, Keck School of Medicine, 
      University of Southern California, Los Angeles, CA 90033 jaeujung@med.usc.edu.
LA  - eng
GR  - R01 HL110609/HL/NHLBI NIH HHS/United States
GR  - AI083025/AI/NIAID NIH HHS/United States
GR  - R01 CA082057/CA/NCI NIH HHS/United States
GR  - CA31363/CA/NCI NIH HHS/United States
GR  - 1F32AI096698/AI/NIAID NIH HHS/United States
GR  - U19 AI083025/AI/NIAID NIH HHS/United States
GR  - R01 CA115284/CA/NCI NIH HHS/United States
GR  - R01 AI073099/AI/NIAID NIH HHS/United States
GR  - P30 DK048522/DK/NIDDK NIH HHS/United States
GR  - R01 CA031363/CA/NCI NIH HHS/United States
GR  - F32 AI096698/AI/NIAID NIH HHS/United States
GR  - R01 CA156330/CA/NCI NIH HHS/United States
GR  - S10 RR022508/RR/NCRR NIH HHS/United States
GR  - R56 AI029564/AI/NIAID NIH HHS/United States
GR  - AI073099/AI/NIAID NIH HHS/United States
GR  - AI029564/AI/NIAID NIH HHS/United States
GR  - P01 CA180779/CA/NCI NIH HHS/United States
GR  - CA156330/CA/NCI NIH HHS/United States
GR  - R01 AI029564/AI/NIAID NIH HHS/United States
GR  - HL110609/HL/NHLBI NIH HHS/United States
GR  - CA082057/CA/NCI NIH HHS/United States
GR  - CA115284/CA/NCI NIH HHS/United States
GR  - R37 AI029564/AI/NIAID NIH HHS/United States
GR  - CA180779/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140623
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (Carrier Proteins)
RN  - 0 (GTPase-Activating Proteins)
RN  - 0 (HOIL-1L protein, mouse)
RN  - 0 (IL1B protein, mouse)
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (NEMO protein, mouse)
RN  - 0 (NF-kappa B)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Nlrp3 protein, mouse)
RN  - 0 (Ralbp1 protein, mouse)
RN  - 0 (Sipl1 protein, mouse)
RN  - EC 2.3.2.27 (Rnf31 protein, mouse)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
CIN - J Exp Med. 2014 Jun 30;211(7):1272. PMID: 24980746
CIN - Nat Rev Immunol. 2014 Sep;14(9):580-1. PMID: 25086647
MH  - Animals
MH  - Carrier Proteins/genetics/*immunology
MH  - Common Variable Immunodeficiency/genetics/immunology
MH  - GTPase-Activating Proteins/genetics/immunology
MH  - Humans
MH  - Immunity, Innate/drug effects/*physiology
MH  - Inflammasomes/genetics/*immunology
MH  - Interleukin-1beta/genetics/immunology
MH  - Intracellular Signaling Peptides and Proteins/genetics/immunology
MH  - Lipopolysaccharides/toxicity
MH  - Macrophages/cytology/*immunology
MH  - Mice
MH  - Mice, Knockout
MH  - Multiprotein Complexes/genetics/*immunology
MH  - NF-kappa B/genetics/immunology
MH  - NLR Family, Pyrin Domain-Containing 3 Protein
MH  - Ubiquitin-Protein Ligases/genetics/immunology
MH  - Ubiquitination/*physiology
PMC - PMC4076580
EDAT- 2014/06/25 06:00
MHDA- 2014/09/05 06:00
PMCR- 2014/12/30
CRDT- 2014/06/25 06:00
PHST- 2014/06/25 06:00 [entrez]
PHST- 2014/06/25 06:00 [pubmed]
PHST- 2014/09/05 06:00 [medline]
PHST- 2014/12/30 00:00 [pmc-release]
AID - jem.20132486 [pii]
AID - 20132486 [pii]
AID - 10.1084/jem.20132486 [doi]
PST - ppublish
SO  - J Exp Med. 2014 Jun 30;211(7):1333-47. doi: 10.1084/jem.20132486. Epub 2014 Jun 
      23.