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PMID: 19136968 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation.

Nature cell biology ·Vol. 11 ·No. 2 ·2009-02-00 ·Pages 123-32

Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S, Yamamoto M, Akira S, Takao T, Tanaka K, Iwai K

Abstract

Nuclear factor-kappaB (NF-kappaB) is a key transcription factor in inflammatory, anti-apoptotic and immune processes. The ubiquitin pathway is crucial in regulating the NF-kappaB pathway. We have found that the LUBAC ligase complex, composed of the two RING finger proteins HOIL-1L and HOIP, conjugates a head-to-tail-linked linear polyubiquitin chain to substrates. Here, we demonstrate that LUBAC activates the canonical NF-kappaB pathway by binding to NEMO (NF-kappaB essential modulator, also called IKKgamma) and conjugates linear polyubiquitin chains onto specific Lys residues in the CC2-LZ domain of NEMO in a Ubc13-independent manner. Moreover, in HOIL-1 knockout mice and cells derived from these mice, NF-kappaB signalling induced by pro-inflammatory cytokines such as TNF-alpha and IL-1beta was suppressed, resulting in enhanced TNF-alpha-induced apoptosis in hepatocytes of HOIL-1 knockout mice. These results indicate that LUBAC is involved in the physiological regulation of the canonical NF-kappaB activation pathway through linear polyubiquitylation of NEMO.

MeSH Terms
Animals Apoptosis/drug effects,physiology Carrier Proteins/genetics,metabolism Cell Line Chimera Cytokines/metabolism,pharmacology Intracellular Signaling Peptides and Proteins/genetics,metabolism Macromolecular Substances/metabolism Mice Mice, Inbred C57BL Mice, Inbred ICR Mice, Knockout Molecular Structure NF-kappa B/genetics,metabolism Polymers/metabolism RING Finger Domains/genetics Ubiquitin/genetics,metabolism Ubiquitin-Conjugating Enzymes/genetics,metabolism Ubiquitin-Protein Ligases/genetics,metabolism Ubiquitination/genetics
Chemicals
Carrier Proteins Cytokines HOIL-1L protein, mouse Intracellular Signaling Peptides and Proteins Macromolecular Substances NEMO protein, mouse NF-kappa B Polymers Ubiquitin Ube2n protein, mouse Ubiquitin-Conjugating Enzymes Rnf31 protein, mouse Ubiquitin-Protein Ligases
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Tokunaga Fuminori
Department of Biophysics and Biochemistry, Graduate School of Medicine and Cell Biology and Metabolism Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
Sakata Shin-ichi
Saeki Yasushi
Satomi Yoshinori
Kirisako Takayoshi
Kamei Kiyoko
Nakagawa Tomoko
Kato Michiko
Murata Shigeo
Yamaoka Shoji
Yamamoto Masahiro
Akira Shizuo
Takao Toshifumi
Tanaka Keiji
Iwai Kazuhiro
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Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb1821
Published
2009-02-00
Epub
2009-00-11
Pages
123-32
Language
English
Region
England
NLM ID
100890575
Subset
IM
Corrections
CommentIn
PMID: 19188917
External Links
PubMed source DOI: 10.1038/ncb1821 View journal details
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