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 gammainducible 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.Major histocompatibility complex (MHC) class II genes encode heterodimeric cell surface molecules that are essential for the presentation of foreign antigenic peptides to helper T cells. Human and mouse genes are expressed in antigen-presenting cells as well as in various cell types upon gamma interferon (IFN-␥) stimulation (16, 34, 52). The expression of these genes occurs mainly at the transcriptional level and is regulated by an array of functional cis elements (H/W, X, and Y) that are conserved among all class II genes (16). Transcription of class II genes is orchestrated by the assembly of a higher-order multiprotein complex on the promoter and requires recruitment of the class II transactivator, CIITA (6, 34). Both constitutive and IFN-␥-inducible expression of class II genes are determined by the presence of CIITA in a variety of cell types (8,34,49). Functional analysis of the structure of CIITA revealed the presence of a C-terminal region required for promoter recruitment (44,59) and an N-terminal acidic transactivation domain that can contact the basic transcriptional machinery (13,35).Recently, we and others have demonstrated that the histone acetylase CREB binding protein (CBP) interacts with CIITA and functions as a coactivator for both B-cell-specific and IFN-␥-induced transcription of MHC class II genes (13, 30). Consequently, expression of MHC class II genes was suppressed by the adenovirus E1A protein (30), which is known to strongly bind to and inhibit CBP action (1, 33).The discovery that transcriptional coactivators have histone acetylase activity (4, 41) provided important insights into the process that links chromatin acetylation to transcriptional activation (20,31,50). CBP/p300 and the associated factor PCAF collaborate with many transcription factors as well as with other coa...

PCAF is a coactivator for p73-mediated transactivation

“…PCAF is a coactivator that enhances the activity of numerous other activators and proteins involved in transcription, including class II transactivator (CIITA) (Spilianakis et al, 2000;Harton et al, 2001), MyoD (Sartorelli et al, 1999;Polesskaya et al, 2000), E2F1 (Martinez-Balbas et al, 2000), TAL1/SCL (Huang et al, 2000), RXR-RAR nuclear receptors (Blanco et al, 1998), E1A (Zhang et al, 2000) and TAF (Muth et al, 2001) and the architectural protein HMGI(Y) (Munshi et al, 2001). PCAF can function alone or together with p300/CBP coactivators through their interaction depending on target promoters.…”

ZXDC, a novel zinc finger protein that binds CIITA and activates MHC gene transcription

“…The N-terminus of CIITA contains a transcriptional activation domain, which binds and recruits to MHC class II gene promoters factors involved in chromatin remodeling and modification, as well as components of the general transcriptional machinery (Fontes et al, 1997(Fontes et al, , 1999Kanazawa et al, 2000;Kanazawa and Peterlin, 2001;Kretsovali et al, 1998;Mahanta et al, 1997;Mudhasani and Fontes, 2002;Spilianakis et al, 2000;Zika et al, 2003). These and other observations have strongly implicated CIITA in regulating chromatin structure as a mechanism of activating gene transcription (Zika and Ting, 2005).…”

Inhibition of human T cell leukemia virus type 2 replication by the suppressive action of class II transactivator and nuclear factor Y

“…CIITA interacts with CBP, p300, PCAF, and the cyclin T1 subunit of the positive transcription elongation factor b to enhance MHC-II gene transcription (51)(52)(53)(54).…”