Principal Role of TRAP/Mediator and SWI/SNF Complexes in Kaposi's Sarcoma-Associated Herpesvirus RTA-Mediated Lytic Reactivation

Abstract

An important step in the herpesvirus life cycle is the switch from latency to lytic reactivation. The RTA transcription activator of Kaposi's sarcoma-associated herpesvirus (KSHV) acts as a molecular switch for lytic reactivation. Here we demonstrate that KSHV RTA recruits CBP, the SWI/SNF chromatin remodeling complex, and the TRAP/Mediator coactivator into viral promoters through interactions with a short acidic sequence in the carboxyl region and that this recruitment is essential for RTA-dependent viral gene expression. The Brg1 subunit of SWI/SNF and the TRAP230 subunit of TRAP/Mediator were shown to interact directly with RTA. Consequently, genetic ablation of these interactions abolished KSHV lytic replication. These results demonstrate that the recruitment of CBP, SWI/SNF, and TRAP/Mediator complexes by RTA is the principal mechanism to direct well-controlled viral gene expression and thereby viral lytic reactivation.

ACKNOWLEDGMENTS

We especially thank S. Gygi at the Harvard Mass Spectrometry facility for mass spectrometry analysis and Yun Kyoung Kang, Etsuko Uno, and Soichiro Yamamura for providing TRAP 230N, TRAP230,and TRAP95 DNAs. We also thank J. Macke for critical reading of the manuscript.

This work was partly supported by U.S. Public Health Service grants CA82057, CA91819, AI38131, and RR00168 and ACS grant RPG0010201. J. Jung is a Leukemia & Lymphoma Society Scholar.