The Histone Acetyltransferase Domains of CREB-binding Protein (CBP) and p300/CBP-associated Factor Are Not Necessary for Cooperativity with the Class II Transactivator

Jenny P.-Y. Ting,Eleni Zika,Jonathan A. Harton

doi:10.1074/jbc.m106652200

Jenny P.-Y. Ting, Eleni Zika + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m106652200

Copy DOI

Abstract

The class II transactivator (CIITA) is a transcriptional co-activator regulating the constitutive and interferon-gamma-inducible expression of class II major histocompatibility complex (MHC) and related genes. Promoter remodeling occurs following CIITA induction, suggesting the involvement of chromatin remodeling factors. Transcription of numerous genes requires the histone acetyltransferase (HAT) activities of CREB-binding protein (CBP), p300, and/or p300/CBP-associated factor (pCAF). These co-activators cooperate with CIITA and are hypothesized to promote class II major histocompatibility complex transcription through their HAT activity. To directly test this, we used HAT-defective CBP and pCAF. We demonstrate that cooperation between CIITA and CBP is independent of CBP HAT activity. Further, although pCAF enhances CIITA-mediated transcription, pCAF HAT domain dependence appears contingent upon the concentration of available CIITA. When HAT-defective CBP and pCAF are both present, cooperativity with CIITA is maintained. Consistent with a recent report, we show that nuclear localization of CIITA is enhanced by lysine 144, an in vitro target of pCAF-mediated HAT. Yet we find that neither mutation of lysine 144 nor deletion of residues 132-209 affects transcriptional cooperation with CBP or pCAF. Thus, acetylation of this residue may not be the primary mechanism for pCAF/CBP cooperation with CIITA. In conclusion, the HAT activities of the co-activators are not necessary for cooperation with CIITA.

Highlights

Expression of class II major histocompatibility complex (MHC)1 molecules is a critical feature of the normal immune response playing a central role in inflammatory, T cell-mediated, and humoral responses through presentation of exogenous, processed antigens to CD4ϩ T cells
We demonstrate that cooperation between class II transactivator (CIITA) and CREB-binding protein (CBP) is independent of CBP histone acetyltransferase (HAT) activity
The ability of CIITA to activate class II MHC transcription can be enhanced by the presence of the co-activators CBP (21, 27), p300/CBP-associated factor (pCAF) (30), or p300 (29)

Summary

Introduction

Expression of class II major histocompatibility complex (MHC) molecules is a critical feature of the normal immune response playing a central role in inflammatory, T cell-mediated, and humoral responses through presentation of exogenous, processed antigens to CD4ϩ T cells. 1 and 2), inducible class II MHC is seen on most class II negative tissues/cells in response to interferon-␥ Both constitutive and inducible class II MHC expression is globally regulated at the transcriptional level by the transcriptional co-activator class II transactivator (CIITA) (reviewed in Ref. 3). CBP/pCAF HAT Domain-independent Transactivation by CIITA co-activators are important for class II MHC transcription, another critical issue is whether the HAT domains of CBP/ pCAF are required for the observed effects. Likewise, it is not clear whether acetylation of CIITA affects its transactivator function. The answers to these issues would greatly affect our view of how CIITA transactivates its target promoters

Methods

Results

Conclusion