title: Downregulation of Poly(ADP-Ribose) Polymerase 1 by a Viral Processivity Factor Facilitates Lytic Replication of Gammaherpesvirus.
abstract: In Kaposi's sarcoma-associated herpesvirus (KSHV), poly(ADP-ribose) polymerase 1 (PARP-1) acts as an inhibitor of lytic replication. Here, we demonstrate that KSHV downregulated PARP-1 upon reactivation. The viral processivity factor of KSHV (PF-8) interacted with PARP-1 and was sufficient to degrade PARP-1 in a proteasome-dependent manner; this effect was conserved in murine gammaherpesvirus 68. PF-8 knockdown in KSHV-infected cells resulted in reduced lytic replication upon reactivation with increased levels of PARP-1, compared to those in control cells. PF-8 overexpression reduced the levels of the poly(ADP-ribosyl)ated (PARylated) replication and transcription activator (RTA) and further enhanced RTA-mediated transactivation. These results suggest a novel viral mechanism for overcoming the inhibitory effect of a host factor, PARP-1, thereby promoting the lytic replication of gammaherpesvirus.
  
  
  
  Gammaherpesviruses are important human pathogens, as they are associated with various kinds of tumors and establish latency mainly in host B lymphocytes. Replication and transcription activator (RTA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is a central molecular switch for lytic replication, and its expression is tightly regulated by many host and viral factors. In this study, we investigated a viral strategy to overcome the inhibitory effect of poly(ADP-ribose) polymerase 1 (PARP-1) on RTA's activity. PARP-1, an abundant multifunctional nuclear protein, was downregulated during KSHV reactivation. The viral processivity factor of KSHV (PF-8) directly interacted with PARP-1 and was sufficient and necessary to degrade PARP-1 protein in a proteasome-dependent manner. PF-8 reduced the levels of PARylated RTA and further promoted RTA-mediated transactivation. As this was also conserved in another gammaherpesvirus, murine gammaherpesvirus 68, our results suggest a conserved viral modulation of a host inhibitory factor to facilitate its lytic replication.
authors.affiliation: Virus-Host Interactions Laboratory, Department of Biosystems and Biotechnology, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Woo-Chang
authors.initials: WC
authors.lastname: Chung
authors.affiliation: Virus-Host Interactions Laboratory, Department of Biosystems and Biotechnology, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Joo-Hee
authors.initials: JH
authors.lastname: Park
authors.affiliation: Virus-Host Interactions Laboratory, Department of Biosystems and Biotechnology, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Hye-Ri
authors.initials: HR
authors.lastname: Kang
authors.affiliation: Virus-Host Interactions Laboratory, Department of Biosystems and Biotechnology, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea moonsong@korea.ac.kr.
authors.forename: Moon Jung
authors.initials: MJ
authors.lastname: Song
mesh_terms: D000818:Animals; D006224:Cricetinae; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D051379:Mice; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis* / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D018144:Rhadinovirus / Q000502:physiology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*
chemical_list: C110348:ORF59 protein, Human herpesvirus 8; D014764:Viral Proteins; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D046988:Proteasome Endopeptidase Complex