Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation

Fuminori Tokunaga; Shin-ichi Sakata; Yasushi Saeki; Yoshinori Satomi; Takayoshi Kirisako; Kiyoko Kamei; Tomoko Nakagawa; Michiko Kato; Shigeo Murata; Shoji Yamaoka; Masahiro Yamamoto; Shizuo Akira; Toshifumi Takao; Keiji Tanaka; Kazuhiro Iwai

doi:10.1038/ncb1821

Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation

Nat Cell Biol. 2009 Feb;11(2):123-32. doi: 10.1038/ncb1821. Epub 2009 Jan 11.

Authors

Fuminori Tokunaga¹, Shin-ichi Sakata, Yasushi Saeki, Yoshinori Satomi, Takayoshi Kirisako, Kiyoko Kamei, Tomoko Nakagawa, Michiko Kato, Shigeo Murata, Shoji Yamaoka, Masahiro Yamamoto, Shizuo Akira, Toshifumi Takao, Keiji Tanaka, Kazuhiro Iwai

Affiliation

¹ 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.

PMID: 19136968
DOI: 10.1038/ncb1821

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Apoptosis / physiology
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Cell Line
Chimera
Cytokines / metabolism
Cytokines / pharmacology
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Macromolecular Substances / metabolism
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Knockout
Molecular Structure
NF-kappa B / genetics
NF-kappa B / metabolism*
Polymers / metabolism
RING Finger Domains / genetics
Ubiquitin / genetics
Ubiquitin / metabolism*
Ubiquitin-Conjugating Enzymes / genetics
Ubiquitin-Conjugating Enzymes / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination* / genetics

Substances

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