Inducible Degradation of IκBα by the Proteasome Requires Interaction with the F-box Protein h-βTrCP*
- Mathias Kroll‡§,
- Florence Margottin¶,
- Alain Kohl‖,
- Patricia Renard‡,
- Hervé Durand¶,
- Jean-Paul Concordet**,
- Françoise Bachelerie‡,
- Fernando Arenzana-Seisdedos‡ and
- Richard Benarous¶‡
- From the ‡Unité d’Immunologie Virale and‖Groupe des Bunyaviridés, Unité des arbovirus et virus des fièvres hémorragiques, Institut Pasteur, 25 et 28, rue du Dr. Roux, 75724 Paris Cedex 15, France and the¶Institut Cochin de Génétique Moléculaire (ICGM) INSERM CJF9703 and **ICGM U129 INSERM, Université Paris V, 75014 Paris, France
Abstract
Activation of NF-κB transcription factors requires phosphorylation and ubiquitin-proteasome-dependent degradation of IκB proteins. We provide evidence that a human F-box protein, h-βTrCP, a component of Skp1-Cullin-F-box protein (SCF) complexes, a new class of E3 ubiquitin ligases, is essential for inducible degradation of IκBα. βTrCP associates with Ser32–Ser36 phosphorylated, but not with unmodified IκBα or Ser32–Ser36phosphorylation-deficient mutants. Expression of a F-box-deleted βTrCP inhibits IκBα degradation, promotes accumulation of phosphorylated Ser32–Ser36 IκBα, and prevents NF-κB-dependent transcription. Our findings indicate that βTrCP is the adaptor protein required for IκBα recognition by the SCFβTrCP E3 complex that ubiquitinates IκBα and makes it a substrate for the proteasome.
Footnotes
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↵* This work was supported in part by the European Union Concerted Action BIOMED II (ROCIO II project), Agence Nationale de Recherche sur le SIDA, SIDACTION, and Association pour la Recherche sur le Cancer (France).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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↵§ Supported by a fellowship of the German Academic Exchange Service (Program HSP III).
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↵‡ To whom correspondence should be addressed. Tel.: 33-1-44-41-25-65; E-mail: benarous{at}cochin.inserm.fr.
- Abbreviations:
- E1
-
ubiquitin-activating enzyme
- E2
-
ubiquitin carrier protein
- E3
-
ubiquitin-protein isopeptide ligase
- SCF
-
Skp1-Cullin-F-box protein
- ConA
-
concanavalin A
- RSV
-
Rous sarcoma virus
- SFV
-
Semliki forest virus
- TNF
-
tumor necrosis factor
- OKA
-
okadaic acid
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- Received December 28, 1998.
- Revision received January 28, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
