title: The cellular peptidyl-prolyl cis/trans isomerase Pin1 regulates reactivation of Kaposi's sarcoma-associated herpesvirus from latency.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma and primary effusion lymphoma. KSHV-infected cells are predominantly latent, with a subset undergoing lytic reactivation. Rta is the essential lytic switch protein that reactivates virus by forming transactivation-competent complexes with the Notch effector protein RBP-Jk and promoter DNA. Strikingly, Rta homolog analysis reveals that prolines constitute 17% of conserved residues. Rta is also highly phosphorylated in vivo. We previously demonstrated that proline content determines Rta homotetramerization and function. We hypothesize that proline-directed modifications regulate Rta function by controlling binding to peptidyl-prolyl cis/trans isomerases (PPIases). Cellular PPIase Pin1 binds specifically to phosphoserine- or phosphothreonine-proline (pS/T-P) motifs in target proteins. Pin1 dysregulation is implicated in myriad human cancers and can be subverted by viruses. Our data show that KSHV Rta protein contains potential pS/T-P motifs and binds directly to Pin1. Rta transactivation is enhanced by Pin1 at two delayed early viral promoters in uninfected cells. Pin1's effect, however, suggests a rheostat-like influence on Rta function. We show that in infected cells, endogenous Pin1 is active during reactivation and enhances Rta-dependent early protein expression induced by multiple signals, as well as DNA replication. Surprisingly, ablation of Pin1 activity by the chemical juglone or dominant-negative Pin1 enhanced late gene expression and production of infectious virus, while ectopic Pin1 showed inhibitory effects. Our data thus suggest that Pin1 is a unique, dose-dependent molecular timer that enhances Rta protein function, but inhibits late gene synthesis and virion production, during KSHV lytic reactivation.
authors.affiliation: Department of Microbiology and Molecular Genetics, New Jersey Medical School and Graduate School of Biomedical Sciences, Rutgers Biomedical and Health Sciences, Rutgers University, Newark, New Jersey, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Guito
authors.forename: Aileen
authors.initials: A
authors.lastname: Gavina
authors.forename: Diana
authors.initials: D
authors.lastname: Palmeri
authors.forename: David M
authors.initials: DM
authors.lastname: Lukac
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004261:DNA Replication; D004279:DNA, Viral / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000737:chemistry / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012514:Sarcoma, Kaposi / Q000821:virology*; D017386:Sequence Homology, Amino Acid; D014775:Virus Activation; D017735:Virus Latency
chemical_list: D004279:DNA, Viral; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse