Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation.
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.
Tokunaga
Fuminori
F
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
S
Saeki
Yasushi
Y
Satomi
Yoshinori
Y
Kirisako
Takayoshi
T
Kamei
Kiyoko
K
Nakagawa
Tomoko
T
Kato
Michiko
M
Murata
Shigeo
S
Yamaoka
Shoji
S
Yamamoto
Masahiro
M
Akira
Shizuo
S
Takao
Toshifumi
T
Tanaka
Keiji
K
Iwai
Kazuhiro
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002678:Chimera; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D015394:Molecular Structure; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011108:Polymers / Q000378:metabolism; D054829:RING Finger Domains / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics
D002352:Carrier Proteins; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D016328:NF-kappa B; D011108:Polymers; D025801:Ubiquitin; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; C514981:NEMO protein, mouse; C514982:Ube2n protein, mouse; C492590:Rnf31 protein, mouse; C000607389:Rbck1 protein, mouse