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NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappaB activation.

ABSTRACT: The mechanism by which the Carma1-Bcl10-MALT1 (CBM) complex couples T cell antigen receptor (TCR) signaling to IkappaB kinase (IKK) and NF-kappaB activation is not known. Here, we show that Bcl10 undergoes K63-linked polyubiquitination in response to T cell activation and subsequently binds NEMO, the regulatory subunit of IKK. This interaction requires the ubiquitin-binding activity of NEMO. The sites of Bcl10 ubiquitination were mapped to K31 and K63. Mutation of these residues did not affect TCR signaling-induced CBM complex assembly but prevented Bcl10 ubiquitination, NEMO binding, and NF-kappaB activation. Therefore, the regulated ubiquitination of Bcl10 and its recognition by NEMO are a critical link between the CBM complex, IKK recruitment, and NF-kappaB activation.

SUBMITTER: Wu CJ

PROVIDER: S-EPMC2268578 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappaB activation.

Wu Chuan-Jin CJ Ashwell Jonathan D JD

Proceedings of the National Academy of Sciences of the United States of America 20080219 8

The mechanism by which the Carma1-Bcl10-MALT1 (CBM) complex couples T cell antigen receptor (TCR) signaling to IkappaB kinase (IKK) and NF-kappaB activation is not known. Here, we show that Bcl10 undergoes K63-linked polyubiquitination in response to T cell activation and subsequently binds NEMO, the regulatory subunit of IKK. This interaction requires the ubiquitin-binding activity of NEMO. The sites of Bcl10 ubiquitination were mapped to K31 and K63. Mutation of these residues did not affect T ...[more]

PMID: 18287044

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Project description:Platelet-activating factor (PAF), a potent proinflammatory phospholipid mediator, has been implicated in inducing intestinal inflammation in diseases such as inflammatory bowel disease (IBD) and necrotizing enterocolitis (NEC). However, its mechanisms of inducing inflammatory responses are not fully understood. Therefore, studies were designed to explore the mechanisms of PAF-induced inflammatory cascade in intestinal epithelial cells.Nuclear factor kappa B (NF-kappaB) activation was measured by luciferase assay and enzyme-linked immunosorbent assay (ELISA), and interleukin 8 (IL-8) production was determined by ELISA. B-cell lymphoma 10 (Bcl10), caspase recruitment domain-containing membrane-associated guanylate kinase protein 3 (CARMA3), and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) mRNA and protein levels were assessed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. siRNA silencing of Bcl10 was used to examine its role in PAF-induced NF-kappaB activation and IL-8 production. The promoter region of the Bcl10 gene was cloned with the PCR method and promoter activity measured by luciferase assay.The adaptor protein Bcl10 appeared to play an important role in the PAF-induced inflammatory pathway in human intestinal epithelial cells. Bcl10 was required for PAF-induced I kappaB alpha phosphorylation, NF-kappaB activation, and IL-8 production in NCM460, a cell line derived from normal human colon, and Caco-2, a transformed human intestinal cell line. PAF also stimulated Bcl10 interactions with CARMA3 and MALT1, and upregulated Bcl10 expression in these cells via transcriptional regulation.These findings highlight a novel PAF-induced inflammatory pathway in intestinal epithelial cells, requiring Bcl10 as a critical mediator and involving CARMA3/Bcl10/MALT1 interactions. The proinflammatory effects of PAF play prominent roles in the pathogenesis of IBD and this pathway may present important targets for intervention in chronic inflammatory diseases of the intestine.

Dataset Information

NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappaB activation.

Publications

NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappaB activation.

Similar Datasets

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