Kruppel-associated box domain-associated protein-1 as a latency regulator for Kaposi's sarcoma-associated herpesvirus and its modulation by the viral protein kinase.
Kaposi's sarcoma-associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma, a major AIDS-associated malignancy, and to hematologic malignancies, including primary effusion lymphoma and multicentric Castleman's disease. Like other herpesviruses, KSHV is capable of both latent and lytic replication. Understanding the molecular details associated with this transition from latency to lytic replication is key to controlling virus spread and can affect the development of intervention strategies. Here, we report that Kruppel-associated box domain-associated protein-1 (KAP-1)/transcriptional intermediary factor 1beta, a cellular transcriptional repressor that controls chromosomal remodeling, participates in the process of switching viral latency to lytic replication. Knockdown of KAP-1 by small interfering RNA leads to KSHV reactivation mediated by K-Rta, a key transcriptional regulator. In cells harboring latent KSHV, KAP-1 was associated with the majority of viral lytic-gene promoters. K-Rta overexpression induced the viral lytic cycle with concomitant reduction of KAP-1 binding to viral promoters. Association of KAP-1 with heterochromatin was modulated by both sumoylation and phosphorylation. During lytic replication of KSHV, KAP-1 was phosphorylated at Ser(824). Several lines of evidence directly linked the viral protein kinase to this post-translational modification. Additional studies showed that this phosphorylation of KAP-1 produced a decrease in its sumoylation, consequently decreasing the ability of KAP-1 to condense chromatin on viral promoters. In summary, the cellular transcriptional repressor KAP-1 plays a role in regulating KSHV latency, and viral protein kinase modulates the chromatin remodeling function of this repressor.
Chang
Pei-Ching
PC
Department of Biological Chemistry and Molecular Medicine and University of California-Davis Cancer Center, California 95817, USA.
Fitzgerald
Latricia D
LD
Van Geelen
Albert
A
Izumiya
Yoshihiro
Y
Ellison
Thomas J
TJ
Wang
Don-Hong
DH
Ann
David K
DK
Luciw
Paul A
PA
Kung
Hsing-Jien
HJ
D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000076183:Tripartite Motif-Containing Protein 28; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication
D017874:Immediate-Early Proteins; D012097:Repressor Proteins; C417604:Rta protein, Human herpesvirus 8; D025841:Small Ubiquitin-Related Modifier Proteins; D015534:Trans-Activators; D014764:Viral Proteins; D049452:Green Fluorescent Proteins; D012694:Serine; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D011494:Protein Kinases