Degradation of Bcl10 induced by T-cell activation negatively regulates NF-kappaB signaling

Item Type:	Article
Title:	Degradation of Bcl10 induced by T-cell activation negatively regulates NF-kappaB signaling
Creators Name:	Scharschmidt, E. and Wegener, E. and Heissmeyer, V. and Rao, A. and Krappmann, D.
Abstract:	Bcl10 is a critical regulator of NF-κB activity in T and B cells, coupling antigen receptor signaling to NF-κB 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-κB transcriptional activity. Bcl10 degradation requires an intact caspase recruitment domain and is not observed after stimulation with tumor necrosis factor α 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-κB activation. Since CD3/CD28-induced activation of JNK is not affected by the decline of Bcl10, degradation of Bcl10, selectively terminates IKK/NF-κB 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.
Keywords:	CD28 Antigens, CD3 Antigens, B-Lymphocytes, Hela Cells, Jurkat Cells, Lymphocyte Activation, Lysosomes, Neoplasm Proteins, NF-kappa B, Signal Transduction, Signal Transducing Adaptor Proteins, T-Cell Antigen Receptors, T-Lymphocytes, Tetradecanoylphorbol Acetate, Transgenic Mice, Ubiquitin, Ubiquitin-Protein Ligases, Animals, Mice
Source:	Molecular and Cellular Biology
ISSN:	0270-7306
Publisher:	American Society for Microbiology
Volume:	24
Number:	9
Page Range:	3860-3873
Date:	1 May 2004
Official Publication:	https://doi.org/10.1128/MCB.24.9.3860-3873.2004
PubMed:	View item in PubMed

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