B cell receptor (BCR) cross-talk: CD40 engagement creates an alternate pathway for BCR signaling that activates I kappa B kinase/I kappa B alpha/NF-kappa B without the need for PI3K and phospholipase C gamma.
BCR signaling is propagated by a series of intermediaries and eventuates in NF-kappaB activation, among other outcomes. Interruption of several mediators that constitute the signalosome, such as PI3K and phospholipase Cgamma2, completely blocks BCR signaling for NF-kappaB. We show here that this accepted, conventional paradigm is, in fact, limited to naive B cells. CD40L treatment reprograms normal B cells such that a novel, alternate pathway for BCR signaling is created. Through this alternate pathway BCR triggering induces nuclear NF-kappaB without the need for PI3K or for phospholipase Cgamma2. Induction of NF-kappaB via the alternate pathway is accompanied by IkappaB kinase beta (IKKbeta) phosphorylation, IkappaBalpha phosphorylation, and IkappaBalpha degradation, and inhibition of IKKbeta blocked IkappaBalpha degradation. Several key events in the conventional pathway, including early protein tyrosine phosphorylation, were unimpeded by generation of the alternate pathway which appears to operate in parallel, rather than in competition, with classical BCR signaling. These results demonstrate cross-talk between CD40 and BCR, such that the requirements for BCR signaling are altered by prior B cell exposure to CD40L. The alternate BCR signaling pathway bypasses multiple signalosome elements and terminates in IKKbeta activation.
Mizuno
Takuya
T
Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Rothstein
Thomas L
TL
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D023201:CD40 Ligand / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020239:Receptor Cross-Talk / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D010738:Type C Phospholipases / Q000378:metabolism / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D019013:CD40 Antigens; D023201:CD40 Ligand; D002352:Carrier Proteins; D002867:Chromones; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D009025:Morpholines; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011947:Receptors, Antigen, B-Cell; D010738:Type C Phospholipases; D014443:Tyrosine; C113939:B cell linker protein; C000606205:Nfkbia protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse