Regulation of the nuclear factor (NF)-kappaB pathway by ISGylation.
Post-translational modification with ISG15 (interferon-stimulated gene 15 kDa) (ISGylation) is mediated by a sequential reaction similar to ubiquitination, and various target proteins for ISGylation have been identified. We previously reported that ISGylation of the E2 ubiquitin-conjugating enzyme Ubc13 suppresses its E2 activity. Ubc13 forms a heterodimer with Uev1A, a ubiquitin-conjugating enzyme variant, and the Ubc13-Uev1A complex catalyzes the assembly of a Lys63-linked polyubiquitin chain, which plays a non-proteolytic role in the nuclear factor (NF)-kappaB pathway. In this study, we examined the effect of ISGylation on tumor necrosis factor receptor-associated factor (TRAF)-6/transforming growth factor beta-activated kinase (TAK)-1-dependent NF-kappaB activation. We found that expression of the ISGylation system suppresses NF-kappaB activation via TRAF6 and TAK1 and that the level of polyubiquitinated TRAF6 is reduced by expression of the ISGylation system. Taken together, the results suggest that the NF-kappaB pathway is negatively regulated by ISGylation.
Minakawa
Miki
M
Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Sone
Takayuki
T
Takeuchi
Tomoharu
T
Yokosawa
Hideyoshi
H
D015153:Blotting, Western; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
D016207:Cytokines; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; D025801:Ubiquitin; D044763:Ubiquitin-Conjugating Enzymes; D014452:Ubiquitins; D000099151:MAP Kinase Kinase Kinase 7; C074034:ISG15 protein, human; C471607:UBE2N protein, human