Regulation of the Nuclear Factor (NF)-.KAPPA.B Pathway by ISGylation

• Published in: Biological & pharmaceutical bulletin Vol. 31; no. 12; pp. 2223 - 2227
• Main Authors: Minakawa, Miki, Sone, Takayuki, Takeuchi, Tomoharu, Yokosawa, Hideyoshi
• Format: Journal Article
• Language: English
• Published: Japan 2008
• Subjects: Blotting, Western; Cell Line; Cytokines - genetics; Cytokines - physiology; Genes, Reporter; Humans; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; NF-kappa B - genetics; NF-kappa B - physiology; RNA Interference; RNA, Small Interfering - pharmacology; Signal Transduction - genetics; Signal Transduction - physiology; TNF Receptor-Associated Factor 6 - metabolism; Ubiquitin - metabolism; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; Ubiquitins - genetics; Ubiquitins - physiology
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.31.2223

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.