Acetylation by PCAF Enhances CIITA Nuclear Accumulation and Transactivation of Major Histocompatibility Complex Class II Genes

Abstract

The class II transactivator (CIITA), the master regulator of the tissue-specific and interferon gamma-inducible expression of major histocompatibility complex class II genes, synergizes with the histone acetylase coactivator CBP to activate gene transcription. Here we demonstrate that in addition to CBP, PCAF binds to CIITA both in vivo and in vitro and enhances CIITA-dependent transcriptional activation of class II promoters. Accordingly, E1A mutants defective for PCAF or CBP interaction show reduced ability in suppressing CIITA activity. Interestingly, CBP and PCAF acetylate CIITA at lysine residues within a nuclear localization signal. We show that CIITA is shuttling between the nucleus and cytoplasm. The shuttling behavior and activity of the protein are regulated by acetylation: overexpression of PCAF or inhibition of cellular deacetylases by trichostatin A increases the nuclear accumulation of CIITA in a manner determined by the presence of the acetylation target lysines. Furthermore, mutagenesis of the acetylated residues reduces the transactivation ability of CIITA. These results support a novel function for acetylation, i.e., to regulate gene expression by stimulating the nuclear accumulation of an activator.

ACKNOWLEDGMENTS

We thank T. Makatounakis and G. Vretzos for providing excellent technical assistance and T. Kouzarides and Y. Nakatani for providing the indicated reagents. We are indebted to D. Thanos for helpful discussions and critical reading of the manuscript. We also thank C. Mamalaki, I. Talianidis, and S. Georgatos for critical reading; Nektaria Kelaidi for help with secretarial work; L. Kalogeraki for photographic work; and T. Makatounakis for assistance with the presentation.

The present work was supported by the Greek Secretariat General for Research through Institutional funds and European Union (EPET II) grant 236.234.603 and National (PENED) grant 2016.