Ubiquitin-dependent degradation of IκBα is mediated by a ubiquitin ligase Skp1/Cul 1/F-box protein FWD1

Shigetsugu Hatakeyama, Masatoshi Kitagawa, Keiko Nakayama, Michiko Shirane, Masaki Matsumoto, Kimihiko Hattori, Hideaki Higashi, Hiroyasu Nakano, Ko Okumura, Kazunori Onoé, Robert A. Good, Kei Ichi Nakayama

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184 Citations (Scopus)


Activation of the transcription factor nuclear factor kappa B (NF-κB) is controlled by proteolysis of its inhibitory subunit (IκB) via the ubiquitin-proteasome pathway. Signal-induced phosphorylation of IκBα by a large multisubunit complex containing IκB kinases is a prerequisite for ubiquitination. Here, we show that FWD1 (a mouse homologue of Slimb/βTrCP), a member of the F-box/WD40-repeat proteins, is associated specifically with IκBα only when IκBα is phosphorylated. The introduction of FWD1 into cells significantly promotes ubiquitination and degradation of IκBα in concert with IκB kinases, resulting in nuclear translocation of NF-κB. In addition, FWD1 strikingly evoked the ubiquitination of IκBα in the in vitro system. In contrast, a dominant-negative form of FWD1 inhibits the ubiquitination, leading to stabilization of IκBα. These results suggest that the substrate-specific degradation of IκBα is mediated by a Skp1/Cull 1/F-box protein (SCF) FWD1 ubiquitin-ligase complex and that FWD1 serves as an intracellular receptor for phosphorylated IκBα. Skp1/Cullin/F-box protein FWD1 might play a critical role in transcriptional regulation of NF- κB through control of IκB protein stability.

Original languageEnglish
Pages (from-to)3859-3863
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number7
Publication statusPublished - Mar 30 1999

All Science Journal Classification (ASJC) codes

  • General


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