NF-kappaB1 and c-Rel cooperate to promote the survival of TLR4-activated B cells by neutralizing Bim via distinct mechanisms.
The nuclear factor-kappaB (NF-kappaB) 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 the result of a failure of the Tpl(2)/MEK/ERK pathway to phosphorylate the proapo-ptotic BH3-only protein Bim and target it for degradation. ERK inactivation of Bim after TLR4 stimulation is accompanied by an increase in A1/Bim and Bcl-x(L)/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-kappaB pathway neutralizing Bim through a combination of Bcl-2 prosurvival protein induction and Tpl2/ERK-dependent Bim phosphorylation and degradation.
Banerjee
Ashish
A
Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Grumont
Raelene
R
Gugasyan
Raffi
R
White
Christine
C
Strasser
Andreas
A
Gerondakis
Steve
S
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology*; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000502:physiology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000502:physiology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4