Common Pathway for the Ubiquitination of IκBα, IκBβ, and IκBε Mediated by the F-Box Protein FWD1*
- Michiko Shirane‡§,
- Shigetsugu Hatakeyama‡§,
- Kimihiko Hattori‡§,
- Keiko Nakayama§¶ and
- Kei-ichi Nakayama‡§¶‖
- From the ‡Department of Molecular and Cellular Biology and ¶Laboratory of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, and§CREST, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan
Abstract
FWD1 (the mouse homolog of DrosophilaSlimb and Xenopus βTrCP, a member of the F-box- and WD40 repeat-containing family of proteins, and a component of the SCF ubiquitin ligase complex) was recently shown to interact with IκBα and thereby to promote its ubiquitination and degradation. This protein has now been shown also to bind to IκBβ and IκBε as well as to induce their ubiquitination and proteolysis. FWD1 was shown to recognize the conserved DSGΨXS motif (where Ψ represents the hydrophobic residue) present in the NH2-terminal regions of these three IκB proteins only when the component serine residues are phosphorylated. However, in contrast to IκBα and IκBβ, the recognition site in IκBε for FWD1 is not restricted to the DSGΨXS motif; FWD1 also interacts with other sites in the NH2-terminal region of IκBε. Substitution of the critical serine residues in the NH2-terminal regions of IκBα, IκBβ, and IκBε with alanines also markedly reduced the extent of FWD1-mediated ubiquitination of these proteins and increased their stability. These data indicate that the three IκB proteins, despite their substantial structural and functional differences, all undergo ubiquitination mediated by the SCFFWD1 complex. FWD1 may thus play an important role in NF-κB signal transduction through regulation of the stability of multiple IκB proteins.
Footnotes
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↵* This work was supported in part by a grant from the Ministry of Education, Science, Sports and Culture of Japan.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‖ To whom correspondence should be addressed: Dept. of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, Fukuoka 812–8582, Japan. Tel.: 81-92-642-6815; Fax.: 81-92-642-6819; E-mail: nakayak1@bioreg.kyushu-u.ac.jp.
- Abbreviations:
- NF-κB
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nuclear factor-κB
- IKK
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IκB kinase
- PAGE
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polyacrylamide gel electrophoresis
- E3
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ubiquitin ligase
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- Received May 24, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
