title: KSHV reactivation from latency requires Pim-1 and Pim-3 kinases to inactivate the latency-associated nuclear antigen LANA.
abstract: Host signal-transduction pathways are intimately involved in the switch between latency and productive infection of herpes viruses. As with other herpes viruses, infection by Kaposi's sarcoma herpesvirus (KSHV) displays these two phases. During latency only few viral genes are expressed, while in the productive infection the virus is reactivated with initiation of extensive viral DNA replication and gene expression, resulting in production of new viral particles. Viral reactivation is crucial for KSHV pathogenesis and contributes to the progression of KS. We have recently identified Pim-1 as a kinase reactivating KSHV upon over-expression. Here we show that another Pim family kinase, Pim-3, also induces viral reactivation. We demonstrate that expression of both Pim-1 and Pim-3 is induced in response to physiological and chemical reactivation in naturally KSHV-infected cells, and we show that they are required for KSHV reactivation under these conditions. Furthermore, our data indicate that Pim-1 and Pim-3 contribute to viral reactivation by phosphorylating the KSHV latency-associated nuclear antigen (LANA) on serine residues 205 and 206. This counteracts the LANA-mediated repression of the KSHV lytic gene transcription. The identification of Pim family kinases as novel cellular regulators of the gammaherpesvirus life cycle facilitates a deeper understanding of virus-host interactions during reactivation and may represent potential novel targets for therapeutic intervention.
authors.affiliation: Genome-Scale Biology Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Fang
authors.initials: F
authors.lastname: Cheng
authors.forename: Magdalena
authors.initials: M
authors.lastname: Weidner-Glunde
authors.forename: Markku
authors.initials: M
authors.lastname: Varjosalo
authors.forename: Eeva-Marja
authors.initials: EM
authors.lastname: Rainio
authors.forename: Anne
authors.initials: A
authors.lastname: Lehtonen
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Schulz
authors.forename: Päivi J
authors.initials: PJ
authors.lastname: Koskinen
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.forename: Päivi M
authors.initials: PM
authors.lastname: Ojala
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014709:Vero Cells; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D000956:Antigens, Viral; D009687:Nuclear Proteins; C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C109540:latency-associated nuclear antigen; D007371:Interferon-gamma; C496634:PIM1 protein, human; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1