Bcl10 activates the NF-κB pathway through ubiquitination of NEMO

Abstract

The NF-kappaB 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-kappaB activation by T- and B-cell receptors. T and B lymphocytes from Bcl10-deficient mice fail to activate NF-kappaB in response to antigen-receptor stimulation and, as a consequence, are unable to proliferate. Bcl10 overexpression is sufficient to activate NF-kappaB, a process that requires the NF-kappaB essential modulator NEMO (also known as IKK-gamma), which is the regulatory subunit of the IkappaB kinase complex. However, the cellular mechanism by which Bcl10 activates the NF-kappaB 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-kappaB activation. Paracaspase and a ubiquitin-conjugating enzyme (UBC13) were both required for Bcl10-induced NEMO ubiquitination and subsequent NF-kappaB 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-kappaB transcription factors through paracaspase- and UBC13-dependent ubiquitination of NEMO.

NF-κB and the immune response

“…It is not yet clear how TCR signaling regulates RIP2 and, in turn, how RIP2 might affect IKK activity. BCL10 oligomerization has been implicated in IKK activation through a process that involves ubiquitination of NEMO (Zhou et al, 2004). This ubiquitination event appears to be mediated by MALT1, and perhaps TRAF6, although no TCR signaling deficits have been reported in TRAF6-deficient mice (Lomaga et al, 1999;Sun et al, 2004).…”

Ubiquitin binding mediates the NF-κB inhibitory potential of ABIN proteins

“…Moreover, we here showed that both the UBAN domain and the NBD of ABIN-1 are involved in its NF-kB inhibitory function ( Figure 3c). NEMO is known to be polyubiquitinated in response to different stimuli including TNF or overexpression of the API2/MALT1 fusion protein involved in MALT lymphoma (Tang et al, 2003;Zhou et al, 2004; Figure 4a). Moreover, ABIN-1 overexpression not only inhibits TNF-induced NF-kB activation, but also API2/MALT1-induced NF-kB activation (Figure 4b).…”

“…NEMO itself was also reported to be ubiquitinated upon different stimuli including TNF and overexpression of the API2/MALT1 fusion protein that is characteristic for certain MALT lymphomas. The functional relevance of the NEMO ubiquitination, however, is still under debate and may also depend on the stimulus (Tang et al, 2003;Zhou et al, 2004Zhou et al, , 2005Shambharkar et al, 2007).…”

Current insights into the regulation of programmed cell death by NF-κB

“…cFLIP potently suppresses death receptor-induced apoptosis, as it blunts activation of pro-caspase-8 and -10 (Micheau et al, 2001;Kreuz et al, 2004). It has recently been shown that cFLIP also participates along with caspase-8 in promoting NF-kB activation via BCL-10, mucosa-associated-lymphoidtissue lymphoma-translocation gene 1 (MALT1) and RIP1 and thus plays a key role in T-cell survival and proliferation following T-cell-receptor stimulation (Abraham and Shaham, 2004;Zhou et al, 2004;Launay et al, 2005, reviewed in Budd et al, 2006. There has been some debate regarding the anti-vs proapoptotic activities of the stress-inducible NF-kB-regulated gene IEX-1 (reviewed in Kucharczak et al, 2003).…”