Transcriptional repression by sumoylation of Epstein-Barr virus BZLF1 protein correlates with association of histone deacetylase.
The transition from latent to lytic phases of the Epstein-Barr virus life cycle is triggered by expression of a viral transactivator, BZLF1, that then induces expression of the viral immediate-early and early genes. The BZLF1 protein is post-translationally modified by a small ubiquitin-related modifier-1 (SUMO-1). Here we found that BZLF1 is conjugated at lysine 12 not only by SUMO-1 but also by SUMO-2 and 3. The K12R mutant of BZLF1, which no longer becomes sumoylated, exhibits stronger transactivation than the wild-type BZLF1 in a reporter assay system as well as in the context of virus genome with nucleosomal structures. Furthermore, exogenous supply of a SUMO-specific protease, SENP, caused de-sumoylation of BZLF1 and enhanced BZLF1-mediated transactivation. Immunoprecipitation experiments proved that histone deacetylase 3 preferentially associated with the sumoylated form of BZLF1. Levels of the sumoylated BZLF1 increased as lytic replication progressed. Based on these observations, we conclude that sumoylation of BZLF1 regulates its transcriptional activity through histone modification during Epstein-Barr virus productive replication.
Division of Virology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
Takayuki
T
Murata
Naoe
N
Hotta
Shigenori
S
Toyama
Sanae
S
Nakayama
Shigeki
S
Chiba
Hiroki
H
Isomura
Takayuki
T
Ohshima
Teru
T
Kanda
Tatsuya
T
Tsurumi
D002460:Cell Line; D045744:Cell Line, Tumor; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D025842:SUMO-1 Protein / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014764:Viral Proteins / Q000235:genetics
C063676:BZLF1 protein, Herpesvirus 4, Human; D025842:SUMO-1 Protein; D015534:Trans-Activators; D014764:Viral Proteins; D006655:Histone Deacetylases