Bruton's tyrosine kinase is required for activation of I kappa B kinase and nuclear factor kappa B in response to B cell receptor engagement

Mutations in the gene encoding Bruton's tyrosine kinase (btk) cause the B c ell deficiency diseases X-linked agammaglobulinemia (XLA) in humans and X-l inked immunodeficiency (xid) in mice. In vivo and in vitro studies indicate that the BTK protein is essential for B cell survival, cell cycle progress ion, and proliferation in response to B cell antigen receptor (BCR) stimula tion. BCR stimulation leads to the activation of transcription factor nucle ar factor (NF)-kappa B, which in turn regulates genes controlling B cell gr owth. We now demonstrate that a null mutation in btk known to cause the rid phenotype prevents BCR-induced activation of NF-kappa B. This defect can b e rescued by reconstitution with wild-type BTK. This mutation also interfer es with BCR-directed activation of I kappa B kinase (IKK), which normally t argets the NF-kappa B inhibitor I kappa B alpha for degradation. Taken toge ther, these findings indicate that BTK couples IKK and NF-kappa B to the BC R. Interference with this coupling mechanism may contribute to the B cell d eficiencies observed in XLA and rid.