This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Scharschmidt, E.
Right arrow Articles by Krappmann, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Scharschmidt, E.
Right arrow Articles by Krappmann, D.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, May 2004, p. 3860-3873, Vol. 24, No. 9
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.9.3860-3873.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Degradation of Bcl10 Induced by T-Cell Activation Negatively Regulates NF-{kappa}B Signaling

Erika Scharschmidt,1 Elmar Wegener,1 Vigo Heissmeyer,2 Anjana Rao,2 and Daniel Krappmann1*

Max Delbrück Center for Molecular Medicine, D-13122 Berlin, Germany,1 Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, Massachusetts 021152

Received 23 September 2003/ Returned for modification 25 November 2003/ Accepted 3 February 2004

Bcl10 is a critical regulator of NF-{kappa}B activity in T and B cells, coupling antigen receptor signaling to NF-{kappa}B activation via protein kinase C (PKC). Here we show that PKC or T-cell receptor (TCR)/CD28 signaling results in downregulation of Bcl10 protein levels, thereby attenuating NF-{kappa}B transcriptional activity. Bcl10 degradation requires an intact caspase recruitment domain and is not observed after stimulation with tumor necrosis factor {alpha} or lipopolysaccharides. Bcl10 downregulation is not affected by proteasome inhibitors but is accompanied by transient localization to lysosomal vesicles, suggesting involvement of the lysosomal pathway rather than the proteasome. The HECT domain ubiquitin ligases NEDD4 and Itch promote ubiquitination and degradation of Bcl10, thus downmodulating NF-{kappa}B activation. Since CD3/CD28-induced activation of JNK is not affected by the decline of Bcl10, degradation of Bcl10 selectively terminates IKK/NF-{kappa}B signaling in response to TCR stimulation. Together, these results suggest a new mechanism of negative signaling in which TCR/PKC signaling initially activates Bcl10 but later promotes its degradation.

* Corresponding author. Mailing address: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany. Phone: 49-30-9406-3751. Fax: 49-30-9406-3884. E-mail: dkrapp{at}mdc-berlin.de.

Molecular and Cellular Biology, May 2004, p. 3860-3873, Vol. 24, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.9.3860-3873.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Moreno-Garcia, M. E., Sommer, K., Haftmann, C., Sontheimer, C., Andrews, S. F., Rawlings, D. J. (2009). Serine 649 Phosphorylation within the Protein Kinase C-Regulated Domain Down-Regulates CARMA1 Activity in Lymphocytes. J. Immunol. 183: 7362-7370 [Abstract] [Full Text]  
  • Li, Z., Wang, H., Xue, L., Shin, D.-M., Roopenian, D., Xu, W., Qi, C.-F., Sangster, M. Y., Orihuela, C. J., Tuomanen, E., Rehg, J. E., Cui, X., Zhang, Q., Morse, H. C. III, Morris, S. W. (2009). E{micro}-BCL10 mice exhibit constitutive activation of both canonical and noncanonical NF-{kappa}B pathways generating marginal zone (MZ) B-cell expansion as a precursor to splenic MZ lymphoma. Blood 114: 4158-4168 [Abstract] [Full Text]  
  • Duwel, M., Welteke, V., Oeckinghaus, A., Baens, M., Kloo, B., Ferch, U., Darnay, B. G., Ruland, J., Marynen, P., Krappmann, D. (2009). A20 Negatively Regulates T Cell Receptor Signaling to NF-{kappa}B by Cleaving Malt1 Ubiquitin Chains. J. Immunol. 182: 7718-7728 [Abstract] [Full Text]  
  • Takeda, K., Harada, Y., Watanabe, R., Inutake, Y., Ogawa, S., Onuki, K., Kagaya, S., Tanabe, K., Kishimoto, H., Abe, R. (2008). CD28 stimulation triggers NF-{kappa}B activation through the CARMA1-PKC{theta}-Grb2/Gads axis. Int Immunol 20: 1507-1515 [Abstract] [Full Text]  
  • Stilo, R., Varricchio, E., Liguoro, D., Leonardi, A., Vito, P. (2008). A20 is a negative regulator of BCL10- and CARMA3-mediated activation of NF-{kappa}B. J. Cell Sci. 121: 1165-1171 [Abstract] [Full Text]  
  • Parravicini, V., Field, A.-C., Tomlinson, P. D., Albert Basson, M., Zamoyska, R. (2008). Itch-/-{alpha}{beta} and {gamma}{delta} T cells independently contribute to autoimmunity in Itchy mice. Blood 111: 4273-7282 [Abstract] [Full Text]  
  • Wu, C.-J., Ashwell, J. D. (2008). NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-{kappa}B activation. Proc. Natl. Acad. Sci. USA 105: 3023-3028 [Abstract] [Full Text]  
  • Zeng, H., Di, L., Fu, G., Chen, Y., Gao, X., Xu, L., Lin, X., Wen, R. (2007). Phosphorylation of Bcl10 Negatively Regulates T-Cell Receptor-Mediated NF-{kappa}B Activation. Mol. Cell. Biol. 27: 5235-5245 [Abstract] [Full Text]  
  • Legarda-Addison, D., Ting, A. T. (2007). Negative Regulation of TCR Signaling by NF-{kappa}B2/p100. J. Immunol. 178: 7767-7778 [Abstract] [Full Text]  
  • Hinz, M., Scheidereit, C. (2007). Striking Back at the Activator: How I{kappa}B Kinase Terminates Antigen Receptor Responses. Sci Signal 2007: pe19-pe19 [Abstract] [Full Text]  
  • Wegener, E., Krappmann, D. (2007). CARD-Bcl10-Malt1 Signalosomes: Missing Link to NF-{kappa}B. Sci Signal 2007: pe21-pe21 [Abstract] [Full Text]  
  • Rueda, D., Gaide, O., Ho, L., Lewkowicz, E., Niedergang, F., Hailfinger, S., Rebeaud, F., Guzzardi, M., Conne, B., Thelen, M., Delon, J., Ferch, U., Mak, T. W., Ruland, J., Schwaller, J., Thome, M. (2007). Bcl10 Controls TCR- and Fc{gamma}R-Induced Actin Polymerization. J. Immunol. 178: 4373-4384 [Abstract] [Full Text]  
  • Koncarevic, A., Jackman, R. W., Kandarian, S. C. (2007). The ubiquitin-protein ligase Nedd4 targets Notch1 in skeletal muscle and distinguishes the subset of atrophies caused by reduced muscle tension. FASEB J. 21: 427-437 [Abstract] [Full Text]  
  • Lobry, C., Lopez, T., Israel, A., Weil, R. (2007). Negative feedback loop in T cell activation through I{kappa}B kinase-induced phosphorylation and degradation of Bcl10. Proc. Natl. Acad. Sci. USA 104: 908-913 [Abstract] [Full Text]  
  • Walker, J. K. L., Ahumada, A., Frank, B., Gaspard, R., Berman, K., Quackenbush, J., Schwartz, D. A. (2006). Multistrain Genetic Comparisons Reveal CCR5 as a Receptor Involved in Airway Hyperresponsiveness. Am. J. Respir. Cell Mol. Bio. 34: 711-718 [Abstract] [Full Text]  
  • Rossman, J. S., Stoicheva, N. G., Langel, F. D., Patterson, G. H., Lippincott-Schwartz, J., Schaefer, B. C. (2006). POLKADOTS Are Foci of Functional Interactions in T-Cell Receptor-mediated Signaling to NF-{kappa}B. Mol. Biol. Cell 17: 2166-2176 [Abstract] [Full Text]  
  • Mittal, A., Papa, S., Franzoso, G., Sen, R. (2006). NF-{kappa}B-Dependent Regulation of the Timing of Activation-Induced Cell Death of T Lymphocytes. J. Immunol. 176: 2183-2189 [Abstract] [Full Text]  
  • Levy, F., Muehlethaler, K., Salvi, S., Peitrequin, A.-L., Lindholm, C. K., Cerottini, J.-C., Rimoldi, D. (2005). Ubiquitylation of a Melanosomal Protein by HECT-E3 Ligases Serves as Sorting Signal for Lysosomal Degradation. Mol. Biol. Cell 16: 1777-1787 [Abstract] [Full Text]  
  • Lynch, O. T., Gadina, M. (2004). Ubiquitination for Activation: New Directions in the NF-{kappa}B Roadmap. Mol. Interv. 4: 144-146 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»