Bcl10 activates the NF-κB pathway through ubiquitination of NEMO

Honglin Zhou, Ingrid Wertz, Karen O'Rourke, Mark Ultsch, Somasekar Seshagiri, Michael Eby, Wei Xiao and Vishva M. Dixit ()
Additional contact information
Honglin Zhou: Genentech Inc. 1 DNA Way
Ingrid Wertz: Genentech Inc. 1 DNA Way
Karen O'Rourke: Genentech Inc. 1 DNA Way
Mark Ultsch: Genentech Inc. 1 DNA Way
Somasekar Seshagiri: Genentech Inc. 1 DNA Way
Michael Eby: Genentech Inc. 1 DNA Way
Wei Xiao: University of Saskatchewan
Vishva M. Dixit: Genentech Inc. 1 DNA Way

Nature, 2004, vol. 427, issue 6970, 167-171

Abstract: 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 stimulation1,2. 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 proliferate3. 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 complex4. 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.

Date: 2004
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DOI: 10.1038/nature02273

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