Submitted October 30, 2007
Accepted August 7, 2008
NF-
B1 and c-Rel cooperate to promote the survival of TLR4 activated B cells by neutralizing Bim via distinct mechanisms
Ashish Banerjee, Raelene Grumont, Raffi Gugasyan, Christine White, Andreas Strasser, and Steve Gerondakis*
The Walter & Eliza Hall Institute of Medical Research, Melbourne, Australia
Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH, United States
* Corresponding author; email: gerondakis{at}burnet.edu.au.
The NF-
B pathway is crucial for the survival of B cells stimulated through Toll-Like Receptors (TLRs). Here we show that the heightened death of TLR4 activated nfkb1-/- B cells is due to a failure of the Tpl2/MEK/ERK pathway to phosphorylate the pro-apoptotic BH3-only protein Bim and target it for degradation. ERK inactivation of Bim following TLR4 stimulation is accompanied by an increase in A1/Bim and Bcl-xL/Bim complexes that we propose represents a c-Rel-dependent mechanism for neutralizing Bim. Together these findings establish that optimal survival of TLR4 activated B cells depends on the NF-B pathway neutralizing Bim through a combination of Bcl-2 pro-survival protein induction and Tpl2/ERK-dependent Bim phosphorylation and degradation.
