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PNAS 104 (3): 908-913

Copyright © 2007 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / IMMUNOLOGY

Negative feedback loop in T cell activation through I{kappa}B kinase-induced phosphorylation and degradation of Bcl10

Camille Lobry, Tatiana Lopez, Alain Israël, and Robert Weil*

Unité de Signalisation Moléculaire et Activation Cellulaire, Unité de Recherche Associée 2582, Centre National de la Recherche Scientifique, Institut Pasteur, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France

Edited by Tak Wah Mak, University of Toronto, Toronto, ON, Canada, and approved November 27, 2006

Received for publication August 11, 2006.

Abstract: Activation of the transcription factor NF-{kappa}B after stimulation through antigen receptors is important for lymphocyte differentiation, activation, proliferation, and protection against apoptosis. Much progress has been made in understanding the molecular events leading to NF-{kappa}B activation, but how this activation is eventually down-regulated is less well understood. Recent studies have indicated that Bcl10 functions downstream of lymphocyte antigen receptors to promote the activation of the I{kappa}B kinase complex leading to the phosphorylation and degradation of the I{kappa}B inhibitors of NF-{kappa}B. Bcl10 has also been implicated in the pathogenesis of mucosa-associated lymphoid tissue lymphoma, possibly in association with its nuclear localization. Here, we provide evidence that the I{kappa}B kinase complex phosphorylates Bcl10 after T cell antigen receptor stimulation and causes its proteolysis via the beta-TrCP ubiquitin ligase/proteasome pathway. These findings document a negative regulatory activity of the IKK complex and suggest that Bcl10 degradation is part of the regulatory mechanisms that precisely control the response to antigens. Mutants of Bcl10 in the IKK phosphorylation site are resistant to degradation, accumulate in the nucleus, and lead to an increase in IL-2 production after T cell antigen receptor stimulation.

Key Words: NF-kB • ubiquitination • signal transduction


Author contributions: C.L. and R.W. designed research; C.L. and T.L. performed research; C.L. and R.W. analyzed data; and C.L., T.L., A.I., and R.W. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS direct submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0606982104/DC1.

*To whom correspondence should be addressed. E-mail: rweil{at}pasteur.fr

© 2007 by The National Academy of Sciences of the USA


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