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Negative feedback loop in T cell activation through IB kinase-induced phosphorylation and degradation of Bcl10
Alain Israël, and
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.
Activation of the transcription factor NF-B after stimulationthrough antigen receptors is important for lymphocyte differentiation,activation, proliferation, and protection against apoptosis.Much progress has been made in understanding the molecular eventsleading to NF-B activation, but how this activation is eventuallydown-regulated is less well understood. Recent studies haveindicated that Bcl10 functions downstream of lymphocyte antigenreceptors to promote the activation of the IB kinase complexleading to the phosphorylation and degradation of the IB inhibitorsof NF-B. Bcl10 has also been implicated in the pathogenesisof mucosa-associated lymphoid tissue lymphoma, possibly in associationwith its nuclear localization. Here, we provide evidence thatthe IB kinase complex phosphorylates Bcl10 after T cell antigenreceptor stimulation and causes its proteolysis via the -TrCPubiquitin ligase/proteasome pathway. These findings documenta negative regulatory activity of the IKK complex and suggestthat Bcl10 degradation is part of the regulatory mechanismsthat precisely control the response to antigens. Mutants ofBcl10 in the IKK phosphorylation site are resistant to degradation,accumulate in the nucleus, and lead to an increase in IL-2 productionafter 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; andC.L., T.L., A.I., and R.W. wrote the paper.