Bcl10 activates the NF-κB pathway through ubiquitination of NEMO

H Zhou, I Wertz, K O'Rourke, M Ultsch, S Seshagiri… - Nature, 2004 - nature.com
H Zhou, I Wertz, K O'Rourke, M Ultsch, S Seshagiri, M Eby, W Xiao, VM Dixit
Nature, 2004nature.com
The NF-κB family of transcription factors is activated in response to many stimuli, including
pro-inflammatory cytokines, environmental stresses and, in the case of B and T lymphocytes,
by antigenic stimulation,. Bcl10 is essential for NF-κB activation by T-and B-cell receptors. T
and B lymphocytes from Bcl10-deficient mice fail to activate NF-κB in response to antigen-
receptor stimulation and, as a consequence, are unable to proliferate. Bcl10 overexpression
is sufficient to activate NF-κB, a process that requires the NF-κB essential modulator NEMO …
Abstract
The NF-κB family of transcription factors is activated in response to many stimuli, including pro-inflammatory cytokines, environmental stresses and, in the case of B and T lymphocytes, by antigenic stimulation,. Bcl10 is essential for NF-κB activation by T- and B-cell receptors. T and B lymphocytes from Bcl10-deficient mice fail to activate NF-κB in response to antigen-receptor stimulation and, as a consequence, are unable to proliferate. Bcl10 overexpression is sufficient to activate NF-κB, a process that requires the NF-κB essential modulator NEMO (also known as IKK-γ), which is the regulatory subunit of the IκB kinase complex. However, the cellular mechanism by which Bcl10 activates the NF-κB pathway remains unclear. Here we show that Bcl10 targets NEMO for lysine-63-linked ubiquitination. Notably, a mutant form of NEMO that cannot be ubiquitinated inhibited Bcl10-induced NF-κB activation. Paracaspase and a ubiquitin-conjugating enzyme (UBC13) were both required for Bcl10-induced NEMO ubiquitination and subsequent NF-κB activation. Furthermore, short interfering RNAs that reduced the expression of paracaspase and UBC13 abrogated the effects of Bcl10. Thus, the adaptor protein Bcl10 promotes activation of NF-κB transcription factors through paracaspase- and UBC13-dependent ubiquitination of NEMO.
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