Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Negative feedback loop in T cell activation through IB 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-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.
The editors suggest the following Related Resources on Science sites:
In Science Signaling
EDITORS' CHOICE
Nancy R. Gough (23 January 2007) Sci. STKE2007 (370), tw28.
[DOI: 10.1126/stke.3702007tw28] |Abstract »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Kinase-Independent Feedback of the TAK1/TAB1 Complex on BCL10 Turnover and NF-{kappa}B Activation.
M. E. Moreno-Garcia, K. Sommer, H. Rincon-Arano, M. Brault, J. Ninomiya-Tsuji, L. E. Matesic, and D. J. Rawlings (2013)
Mol. Cell. Biol.
33, 1149-1163
|Abstract »|Full Text »|PDF »
A Quantitative Signaling Screen Identifies CARD11 Mutations in the CARD and LATCH Domains That Induce Bcl10 Ubiquitination and Human Lymphoma Cell Survival.
W. Chan, T. B. Schaffer, and J. L. Pomerantz (2013)
Mol. Cell. Biol.
33, 429-443
|Abstract »|Full Text »|PDF »
Chronic Activation of the Kinase IKK{beta} Impairs T Cell Function and Survival.
S. Krishna, D. Xie, B. Gorentla, J. Shin, J. Gao, and X.-P. Zhong (2012)
J. Immunol.
189, 1209-1219
|Abstract »|Full Text »|PDF »
Cutting Edge: The "Death" Adaptor CRADD/RAIDD Targets BCL10 and Suppresses Agonist-Induced Cytokine Expression in T Lymphocytes.
Q. Lin, Y. Liu, D. J. Moore, S. K. Elizer, R. A. Veach, J. Hawiger, and H. E. Ruley (2012)
J. Immunol.
188, 2493-2497
|Abstract »|Full Text »|PDF »
Antigen Receptor Signaling to NF-{kappa}B via CARMA1, BCL10, and MALT1.
M. Thome, J. E. Charton, C. Pelzer, and S. Hailfinger (2010)
Cold Spring Harb Perspect Biol
2, a003004
|Abstract »|Full Text »|PDF »
Interplay between BCL10, MALT1 and I{kappa}B{alpha} during T-cell-receptor-mediated NF{kappa}B activation.
G. Carvalho, A. Le Guelte, C. Demian, A. Vazquez, J. Gavard, and N. Bidere (2010)
J. Cell Sci.
123, 2375-2380
|Abstract »|Full Text »|PDF »
The IKK Complex, a Central Regulator of NF-{kappa}B Activation.
MAGUK-Controlled Ubiquitination of CARMA1 Modulates Lymphocyte NF-{kappa}B Activity.
M. E. Moreno-Garcia, K. Sommer, H. Shinohara, A. D. Bandaranayake, T. Kurosaki, and D. J. Rawlings (2010)
Mol. Cell. Biol.
30, 922-934
|Abstract »|Full Text »|PDF »
On to the road to degradation: atherosclerosis and the proteasome.
J. Herrmann, L. O. Lerman, and A. Lerman (2010)
Cardiovasc Res
85, 291-302
|Abstract »|Full Text »|PDF »
Serine 649 Phosphorylation within the Protein Kinase C-Regulated Domain Down-Regulates CARMA1 Activity in Lymphocytes.
M. E. Moreno-Garcia, K. Sommer, C. Haftmann, C. Sontheimer, S. F. Andrews, and D. J. Rawlings (2009)
J. Immunol.
183, 7362-7370
|Abstract »|Full Text »|PDF »
Inflammatory NF-{kappa}B activation promotes hepatic apolipoprotein B100 secretion: evidence for a link between hepatic inflammation and lipoprotein production.
J. Tsai, R. Zhang, W. Qiu, Q. Su, M. Naples, and K. Adeli (2009)
Am J Physiol Gastrointest Liver Physiol
296, G1287-G1298
|Abstract »|Full Text »|PDF »
Compensatory IKK{alpha} activation of classical NF-{kappa}B signaling during IKK{beta} inhibition identified by an RNA interference sensitization screen.
L. T. Lam, R. E. Davis, V. N. Ngo, G. Lenz, G. Wright, W. Xu, H. Zhao, X. Yu, L. Dang, and L. M. Staudt (2008)
PNAS
105, 20798-20803
|Abstract »|Full Text »|PDF »
I{kappa}B kinase induced phosphorylation of CARMA1 contributes to CARMA1 Bcl10 MALT1 complex formation in B cells.
H. Shinohara, S. Maeda, H. Watarai, and T. Kurosaki (2007)
J. Exp. Med.
204, 3285-3293
|Abstract »|Full Text »|PDF »
Striking Back at the Activator: How I{kappa}B Kinase Terminates Antigen Receptor Responses.
B kinase-induced phosphorylation and degradation of Bcl10
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-
-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. 
