Induction of Immunoglobulin Heavy-Chain Transcription through the Transcription Factor Bright Requires TFII-I

Abstract

Bright/ARID3a/Dril1, a member of the ARID family of transcription factors, is expressed in a highly regulated fashion in B lymphocytes, where it enhances immunoglobulin transcription three- to sixfold. Recent publications from our lab indicated that functional, but not kinase-inactive, Bruton's tyrosine kinase (Btk) is critical for Bright activity in an in vitro model system, yet Bright itself is not appreciably tyrosine phosphorylated. These data suggested that a third protein, and Btk substrate, must contribute to Bright-enhanced immunoglobulin transcription. The ubiquitously expressed transcription factor TFII-I was identified as a substrate for Btk several years ago. In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels. These data suggest that Bright functions as a three-component protein complex in the immunoglobulin locus and tie together previous data indicating important roles for Btk and TFII-I in B lymphocytes.

We thank A. Windell and T. D. Ashworth for technical assistance, S. Hutchinson for TFII-I purification, X.-H. Sun for critically reading the manuscript, and K. Humphrey for help in its preparation.

This work was supported by the USIDNET and NIH grants AI044215 (C.F.W.) and AI45150 (A.L.R.). This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program grant C06 RR14570-01 from the National Center for Research Resources, National Institutes of Health.