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Sci. STKE, 23 January 2007
Vol. 2007, Issue 370, p. tw28
[DOI: 10.1126/stke.3702007tw28]

EDITORS' CHOICE

Immunology Applying the Brakes to the Immune Response

Nancy R. Gough

Science's STKE, AAAS, Washington, DC 20005, USA

Activation of the inflammatory response mediated by the transcription factor nuclear factor {kappa}B (NF-{kappa}B) is a one-way street, because activation involves the phosphorylation (by the kinase complex IKK) and ubiquitin-mediated degradation of the protein (I{kappa}B) that sequesters NF-{kappa}B in the cytosol to inhibit its activity. In T and B cells, a signaling adaptor complex consisting of CARMA1 [caspase recruitment domain (CARD) 11], Bcl10, and MALT1 connects receptor activation to activation of IKK, I{kappa}B degradation, and NF-{kappa}B translocation to the nucleus to activate proinflammatory gene expression. Lobry et al. provide evidence from cultured T cell lines that IKK also phosphorylates Bcl10, which leads to its ubiquitination and proteasome-mediated degradation, thereby providing a mechanism by which the extent of NF-{kappa}B activation can be limited. Degradation of Bcl10 in response to T cell receptor ligation or phorbol esters (which directly activate protein kinase C, bypassing the receptor) was inhibited in Jurkat cells deficient for CARMA1 or NEMO (which is a regulatory component of the IKK complex), which suggested that activation of the pathway through IKK was required. Pharmacological inhibition of IKK or down-regulation of IKKbeta by RNA interference (RNAi) also prevented Bcl10 degradation. (IKKbeta is one of two IKK isoforms; RNAi for IKK{alpha} was less effective at inhibiting phosphorylation of Bcl10.) Overexpression of tagged Bcl10 with tagged IKKbeta resulted in the accumulation of slower migrating forms of Bcl10, and phosphatase treatment suggested that these were phosphorylated forms of Bcl10. In vitro assays confirmed that IKKbeta directly phosphorylated Bcl10, and mutational analysis identified several phosphorylation sites including two (Thr81 and Ser85) that were in a consensus recognition sequence for phosphorylation-mediated binding of the ubiquitin ligase beta-transducin repeat-containing protein (beta-TrCP). In transfected HEK293 cells, Bcl10 and beta-TrCP were coimmunoprecipitated when active IKKbeta was also expressed. Two mutant forms of Bcl10, in which Thr81 was replaced by Ala (T81A) and Ser85 by Ala (S85A), did not interact with beta-TrCP, and this mutant was also resistant to T cell receptor-stimulated degradation. Interleukin 2 production was enhanced in T cell lines (E29.1) expressing the T81A and S85A mutant compared with cells expressing wild-type Bcl10; thus, Bcl10 degradation appears to limit NF-{kappa}B signaling. Finally, two different IKK phosphorylation-deficient mutant forms of Bcl10 accumulated in the nucleus after T cell receptor stimulation. This is intriguing because this localization has also been noted in mucosa-associated lymphoid tissue (MALT) lymphoma. The results regarding Bcl10 phosphorylation reported here are not entirely consistent with other studies and it may be that, under different conditions, different regulatory mechanisms involving Bcl10 exist.

C. Lobry, T. Lopez, A. Israël, R. Weil, 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 (2007). [Abstract] [Full Text]

Citation: N. R. Gough, Applying the Brakes to the Immune Response. Sci. STKE 2007, tw28 (2007).



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