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Activation of NF-κB in B cell receptor signaling through Bruton’s tyrosine kinase-dependent phosphorylation of IκB-α

  • Pontoriero, Marilena1
  • Fiume, Giuseppe1
  • Vecchio, Eleonora1
  • de Laurentiis, Annamaria1
  • Albano, Francesco1
  • Iaccino, Enrico1
  • Mimmi, Selena1
  • Pisano, Antonio1
  • Agosti, Valter1
  • Giovannone, Emilia1
  • Altobelli, Annalisa2
  • Caiazza, Carmen2
  • Mallardo, Massimo2
  • Scala, Giuseppe1
  • Quinto, Ileana1
  • 1 University of Catanzaro “Magna Græcia”, Department of Clinical and Experimental Medicine, Viale Europa, Germaneto, Catanzaro, 88100, Italy , Catanzaro (Italy)
  • 2 University of Naples “Federico II”, Department of Molecular Medicine and Medical Biotechnology, Via S. Pansini, Naples, 80131, Italy , Naples (Italy)
Published Article
Journal of Molecular Medicine
Publication Date
Mar 19, 2019
DOI: 10.1007/s00109-019-01777-x
Springer Nature


AbstractThe antigen-mediated triggering of B cell receptor (BCR) activates the transcription factor NF-κB that regulates the expression of genes involved in B cell differentiation, proliferation, and survival. The tyrosine kinase Btk is essentially required for the activation of NF-κB in BCR signaling through the canonical pathway of IKK-dependent phosphorylation and proteasomal degradation of IκB-α, the main repressor of NF-κB. Here, we provide the evidence of an additional mechanism of NF-κB activation in BCR signaling that is Btk-dependent and IKK-independent. In DeFew B lymphoma cells, the anti-IgM stimulation of BCR activated Btk and NF-κB p50/p65 within 0.5 min in absence of IKK activation and IκB-α degradation. IKK silencing did not affect the rapid activation of NF-κB. Within this short time, Btk associated and phosphorylated IκB-α at Y289 and Y305, and, concomitantly, p65 translocated from cytosol to nucleus. The mutant IκB-α Y289/305A inhibited the NF-κB activation after BCR triggering, suggesting that the phosphorylation of IκB-α at tyrosines 289 and 305 was required for NF-κB activation. In primary chronic lymphocytic leukemia cells, Btk was constitutively active and associated with IκB-α, which correlated with Y305-phosphorylation of IκB-α and increased NF-κB activity compared with healthy B cells. Altogether, these results describe a novel mechanism of NF-κB activation in BCR signaling that could be relevant for Btk-targeted therapy in B-lymphoproliferative disorders.Key messagesAnti-IgM stimulation of BCR activates NF-κB p50/p65 within 30 s by a Btk-dependent and IKK-independent mechanism.Btk associates and phosphorylates IκB-α at Y289 and Y305, promoting NF-κB activation.In primary CLLs, the binding of Btk to IκB-α correlates with tyrosine phosphorylation of IκB-α and increased NF-κB activity.

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