Kaposi's sarcoma-associated herpesvirus transactivator RTA promotes degradation of the repressors to regulate viral lytic replication.
Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) RTA is an important protein involved in the induction of KSHV lytic replication from latency through activation of the lytic cascade. A number of cellular and viral proteins, including K-RBP, have been found to repress RTA-mediated transactivation and KSHV lytic replication. However, it is unclear as to how RTA overcomes the suppression during lytic reactivation. In this study, we found that RTA can induce K-RBP degradation through the ubiquitin-proteasome pathway and that two regions in RTA are responsible. Moreover, we found that RTA can promote the degradation of several other RTA repressors. RTA mutants that are defective in inducing K-RBP degradation cannot activate RTA responsive promoter as efficiently as wild-type RTA. Interference of the ubiquitin-proteasome pathway affected RTA-mediated transactivation and KSHV reactivation from latency. Our results suggest that KSHV RTA can stimulate the turnover of repressors to modulate viral reactivation. Since herpes simplex virus type 1 transactivator ICP0 and human cytomegalovirus transactivator pp71 also stimulate the degradation of cellular silencers, it is possible that the promotion of silencer degradation by viral transactivators may be a common mechanism for regulating the lytic replication of herpesviruses.
Yang
Zhilong
Z
Nebraska Center for Virology and School of Biological Sciences, University of Nebraska, E249 Beadle Center, P.O. Box 880666, Lincoln, NE 68588-0666, USA.
Yan
Zhangcai
Z
Wood
Charles
C
D000956:Antigens, Viral / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D002460:Cell Line; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D017384:Sequence Deletion; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014775:Virus Activation
D000956:Antigens, Viral; D050976:Basic-Leucine Zipper Transcription Factors; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators; D014764:Viral Proteins; C520977:ZNF426 protein, human; C109540:latency-associated nuclear antigen; D046988:Proteasome Endopeptidase Complex