BANK1 controls CpG-induced IL-6 secretion via a p38 and MNK1/2/eIF4E translation initiation pathway.
BANK1, an adaptor protein expressed in B cells, plays a little understood role in B cell signaling. Because BANK1 contains an N-terminal putative Toll/IL-1R receptor domain, we used mouse Bank1(-/-) splenic B cells to test whether BANK1 affects signaling induced by the TLR9 agonist CpG. Following CpG stimulation, BANK1 deficiency reduced p38 phosphorylation without affecting that of ERK or JNK and reduced IL-6 secretion. Bank1(-/-) B cells showed reduced phosphorylation of MNK1/2 and eIF4E, suggesting an effect on translation initiation, whereas Bank1(-/-) had no effect on IL-6 mRNA stability, thus suggesting that BANK1 has no effect on MK2 signaling. IL-6 secretion observed when CpG stimulation was combined with anti-CD40 was reduced in the absence of BANK1. Whereas in the presence of anti-CD40 stimulation CpG induced a stronger phosphorylation of AKT, mTOR, and 4E-BP1, Bank1(-/-) had no effect on phosphorylation of mTOR and 4E-BP1, and a weak effect on AKT, implying that BANK1 does not affect the release of eIF4E by phospho-4E-BP1. Taken together, these data establish a previously unrecognized role for BANK1 in CpG-induced responses by splenic B cells on p38 signaling and control of translation initiation of IL-6 via MNK1/2 and eIF4E.
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.
Ying-Yu
YY
Wu
Ramesh
R
Kumar
Mohammed Shamsul
MS
Haque
Casimiro
C
Castillejo-López
Marta E
ME
Alarcón-Riquelme
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D018899:CpG Islands / Q000276:immunology*; D004789:Enzyme Activation; D039561:Eukaryotic Initiation Factor-4E / Q000502:physiology*; D039642:Eukaryotic Initiation Factors; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010442:Peptide Chain Initiation, Translational / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology; D000099190:MAP-Kinase-Activated Kinase 2
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C586431:BANK1 protein, mouse; C499527:Eif4ebp1 protein, mouse; C577686:interleukin-6, mouse; C106281:Mknk1 protein, mouse; C106282:Mknk2 protein, mouse; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse