Regulation of nuclear localization and transcriptional activity of TFII-I by Bruton's tyrosine kinase

Bruton's tyrosine kinase (Btk) is required for normal B-cell development, a s defects in Btk lead to X-linked immunodeficiency (xid) in mice and X-link ed agammaglobulinemia (XLA) in humans. Here we demonstrate a functional int eraction between the multifunctional transcription factor TFII-I and Btk. E ctopic expression of wild-type Btk enhances TFII-I-mediated transcriptional activation and its tyrosine phosphorylation in transient-transfection assa ys. Mutation of Btk in either the PH domain (R28C, as in the murine rid mut ation) or the kinase domain (K430E) compromises its ability to enhance both the tyrosine phosphorylation and the transcriptional activity of TFII-I. T FII-I associates constitutively in vivo with wild-type Btk and kinase-inact ive Btk but not rid Btk. However, membrane immunoglobulin M cross-linking i n B cells leads to dissociation of TFII-I from Btk. We further show that wh ile TFII-I is found in both the nucleus and cytoplasm of wild-type and rid primary resting B cells, nuclear TFII-I is greater in rid B cells. Most str ikingly, receptor cross linking of wild-type (but not xid) B cells results in increased nuclear import of TFII-I. Taken together, these data suggest t hat although the PH domain of Btk is primarily responsible for its physical interaction with TFII-I, an intact kinase domain of Btk is required to enh ance transcriptional activity of TFII-I in the nucleus. Thus, mutations imp airing the physical and/or functional association between TFII-I and Btk ma y result in diminished TFII-I-dependent transcription and contribute to def ective B-cell development and/or function.