Acetylation by PCAF enhances CIITA nuclear accumulation and transactivation of major histocompatibility complex class II genes.
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.
Spilianakis
C
C
Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology, Heraklion, Crete, Greece.
Papamatheakis
J
J
Kretsovali
A
A
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D050882:CREB-Binding Protein; D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D028884:Karyopherins; D009154:Mutation; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000097606:Exportin 1 Protein
D000123:Acetyltransferases; D017500:Adenovirus E1A Proteins; D050882:CREB-Binding Protein; D002352:Carrier Proteins; D051548:Histone Acetyltransferases; D028884:Karyopherins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D000097606:Exportin 1 Protein; C083728:MHC class II transactivator protein; C494363:CREBBP protein, human