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.


Logo for

PNAS 104 (3): 908-913

Copyright © 2007 by the National Academy of Sciences.


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

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

© 2007 by The National Academy of Sciences of the USA

The I{kappa}B kinase complex in NF-{kappa}B regulation and beyond.
M. Hinz and C. Scheidereit (2014)
EMBO Rep. 15, 46-61
   Abstract »    Full Text »    PDF »
Regulation of T cell function by the ubiquitin-specific protease USP9X via modulating the Carma1-Bcl10-Malt1 complex.
Y. Park, H.-s. Jin, and Y.-C. Liu (2013)
PNAS 110, 9433-9438
   Abstract »    Full Text »    PDF »
Amot130 Adapts Atrophin-1 Interacting Protein 4 to Inhibit Yes-associated Protein Signaling and Cell Growth.
J. J. Adler, B. L. Heller, L. R. Bringman, W. P. Ranahan, R. R. Cocklin, M. G. Goebl, M. Oh, H.-S. Lim, R. J. Ingham, and C. D. Wells (2013)
J. Biol. Chem. 288, 15181-15193
   Abstract »    Full Text »    PDF »
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.
A. Israel (2010)
Cold Spring Harb Perspect Biol 2, a000158
   Abstract »    Full Text »    PDF »
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 »
COP9 signalosome controls the Carma1-Bcl10-Malt1 complex upon T-cell stimulation.
V. Welteke, A. Eitelhuber, M. Duwel, K. Schweitzer, M. Naumann, and D. Krappmann (2009)
EMBO Rep. 10, 642-648
   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.
M. Hinz and C. Scheidereit (2007)
Sci. STKE 2007, pe19
   Abstract »    Full Text »    PDF »
CARD-Bcl10-Malt1 Signalosomes: Missing Link to NF-{kappa}B.
E. Wegener and D. Krappmann (2007)
Sci. STKE 2007, pe21
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882