Poly(ADP-ribose) polymerase 1 and Ste20-like kinase hKFC act as transcriptional repressors for gamma-2 herpesvirus lytic replication.
The replication and transcription activator (RTA) of gamma-2 herpesvirus is sufficient to drive the entire virus lytic cycle. Hence, the control of RTA activity should play an important role in the maintenance of viral latency. Here, we demonstrate that cellular poly(ADP-ribose) polymerase 1 (PARP-1) and Ste20-like kinase hKFC interact with the serine/threonine-rich region of gamma-2 herpesvirus RTA and that these interactions efficiently transfer poly(ADP-ribose) and phosphate units to RTA. Consequently, these modifications strongly repressed RTA-mediated transcriptional activation by inhibiting its recruitment onto the promoters of virus lytic genes. Conversely, the genetic ablation of PARP-1 and hKFC interaction or the knockout of the PARP-1 gene and activity considerably enhanced gamma-2 herpesvirus lytic replication. Thus, this is the first demonstration that cellular PARP-1 and hKFC act as molecular sensors to regulate RTA activity and thereby, herpesvirus latency.
Department of Microbiology and Molecular Genetics, Tumor Virology Division, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Drive, Southborough, MA 01772-9102, USA.
Yousang
Y
Gwack
Hiroyuki
H
Nakamura
Sun Hwa
SH
Lee
John
J
Souvlis
Jason T
JT
Yustein
Steve
S
Gygi
Hsing-Jien
HJ
Kung
Jae U
JU
Jung
D002460:Cell Line; D018142:Gammaherpesvirinae / Q000235:genetics / Q000502:physiology*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
D011994:Recombinant Proteins; D012097:Repressor Proteins; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases