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PMID: 15082780 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Degradation of Bcl10 induced by T-cell activation negatively regulates NF-kappa B signaling.

Molecular and cellular biology ·Vol. 24 ·No. 9 ·2004-05-00 ·Pages 3860-73

Scharschmidt E, Wegener E, Heissmeyer V, Rao A, Krappmann D

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing Animals B-Cell CLL-Lymphoma 10 Protein B-Lymphocytes/immunology,metabolism CD28 Antigens/metabolism CD3 Complex/metabolism Endosomal Sorting Complexes Required for Transport HeLa Cells Humans Jurkat Cells Lymphocyte Activation Lysosomes/metabolism Mice Mice, Transgenic NF-kappa B/metabolism Nedd4 Ubiquitin Protein Ligases Neoplasm Proteins/metabolism Receptors, Antigen, T-Cell/metabolism Signal Transduction/physiology T-Lymphocytes/drug effects,immunology,metabolism Tetradecanoylphorbol Acetate/pharmacology Ubiquitin/metabolism Ubiquitin-Protein Ligases/metabolism
Chemicals
Adaptor Proteins, Signal Transducing B-Cell CLL-Lymphoma 10 Protein BCL10 protein, human Bcl10 protein, mouse CD28 Antigens CD3 Complex Endosomal Sorting Complexes Required for Transport NF-kappa B Neoplasm Proteins Receptors, Antigen, T-Cell Ubiquitin Itch protein, mouse Nedd4 Ubiquitin Protein Ligases Nedd4 protein, human Nedd4l protein, mouse Ubiquitin-Protein Ligases Tetradecanoylphorbol Acetate
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Scharschmidt Erika
Max Delbrück Center for Molecular Medicine, D-13122 Berlin, Germany.
Wegener Elmar
Heissmeyer Vigo
Rao Anjana
Krappmann Daniel
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.9.3860-3873.2004
Published
2004-05-00
Pages
3860-73
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC387748
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.24.9.3860-3873.2004 PMC Full Text View journal details
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