BAFF regulates B cell survival by downregulating the BH3-only family member Bim via the ERK pathway.
The B cell activating factor belonging to the tumor necrosis factor family (BAFF) is required for B cell survival and maturation. The mechanisms by which BAFF mediates B cell survival are less understood. We found that BAFF and a proliferation-inducing ligand (APRIL), which are related, block B cell antigen receptor (BCR)-induced apoptosis upstream of mitochondrial damage, which is consistent with a role for Bcl-2 family proteins. BCR ligation strongly increased expression of the proapoptotic Bcl-2 homology 3-only Bcl-2 protein Bim in both WEHI-231 and splenic B cells, and increases in Bim were reversed by BAFF or APRIL. Small interfering RNA vector-mediated suppression of Bim blocked BCR-induced apoptosis. BAFF also induced Bim phosphorylation and inhibited BCR-induced association of Bim with Bcl-2. BAFF induced delayed but sustained stimulation of extracellular signal-regulated kinase (ERK) and its activators, mitogen-activated protein kinase/ERK activating kinase (MEK) and c-Raf, and MEK inhibitors promoted accumulation and dephosphorylation of Bim. These results suggest that BAFF inhibits BCR-induced death by down-regulating Bim via sustained ERK activation, demonstrating that BAFF directly regulates Bim function. Although transitional immature type 1 (T1) B cell numbers are normal in Bim(-/-) mice, T2 and follicular mature B cells are elevated and marginal zone B cells are reduced. Our results suggest that mature B cell homeostasis is maintained by BAFF-mediated regulation of Bim.
Craxton
Andrew
A
Department of Microbiology, University of Washington, Seattle, WA 98195, USA. andyuk@u.washington.edu
Draves
Kevin E
KE
Gruppi
Adriana
A
Clark
Edward A
EA
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D053264:B-Cell Activating Factor; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D013154:Spleen / Q000166:cytology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D053264:B-Cell Activating Factor; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; C505720:Tnfsf13b protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases