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International Immunology, Vol. 15, No. 10, pp. 1195-1205, October 2003
© 2003 Japanese Society for Immunology

Phosphorylation of class II transactivator regulates its interaction ability and transactivation function

Tyler J. Sisk1, Kevin Nickerson1, Roland P. S. Kwok2,3 and Cheong-Hee Chang4

Departments of 1 Microbiology and Immunology, 2 Obstetrics and Gynecology and 3 Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA 4 Department of Microbiology and Immunology, Indiana University, 950 W. Walnut Street, Indianapolis, IN 46202, USA

Correspondence to: C.-H. Chang; E-mail: chechang{at}iupui.edu
Transmitting editor: L. Glimcher

The MHC class II transactivator (CIITA) plays a central role in adaptive immune responses by controlling the expression of MHC class II genes. CIITA binds DNA-binding proteins and co-activator proteins to form an enhanceosome complex necessary for MHC class II gene expression. Here we demonstrate that CIITA interactions depend upon the phosphorylation status of CIITA. Hyper-phosphorylated CIITA interacts with co-activator p300, RFX5 and CIITA itself, which in turn results in induction of MHC class II promoter activity. Moreover, the C-terminal region of CIITA containing leucine-rich repeats (LRR) is a regulatory domain for CIITA self-association and LRR binding to CIITA is negatively regulated by phosphorylation. cAMP-dependent protein kinase (PKA) phosphorylates CIITA, and serine residues residing in a region between the proline/serine/threonine-rich domain and the GTP-binding domain are phosphorylated by PKA in vitro. The maximum transactivation potential of CIITA requires PKA phosphorylation as demonstrated by reduced transactivation activities of the mutant bearing substitutions of serine residues at the PKA site.

Keywords: gene regulation, MHC, protein kinase, transcription factor


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