title: Herpesvirus saimiri antagonizes nuclear domain 10-instituted intrinsic immunity via an ORF3-mediated selective degradation of cellular protein Sp100.
abstract: In recent studies, the nuclear domain 10 (ND10) components PML, Sp100, human Daxx (hDaxx), and ATRX were identified to be cellular restriction factors that are able to inhibit the replication of several herpesviruses. The antiviral function of ND10, however, is antagonized by viral effector proteins by a variety of strategies, including degradation of PML or relocalization of ND10 proteins. In this study, we analyzed the interplay between infection with herpesvirus saimiri (HVS), the prototypic rhadinovirus, and cellular defense by ND10. In contrast to other herpesviruses, we found that HVS specifically degraded the cellular ND10 component Sp100, whereas other factors like PML or hDaxx remained intact. We could further identify the ORF3 tegument protein of HVS, which shares homology with the cellular formylglycinamide ribotide amidotransferase (FGARAT) enzyme, to be the viral factor that induces the proteasomal degradation of Sp100. Interestingly, recent studies showed that the ORF3-homologous proteins ORF75c of murine gammaherpesvirus 68 and BNRF-1 of Epstein-Barr virus modulate the ND10 proteins PML and ATRX, respectively, suggesting that the ND10 targets of viral FGARAT-homologous proteins diversified during evolution. Furthermore, a virus with the ORF3 deletion was efficiently complemented in Sp100-depleted cells, indicating that Sp100 is able to inhibit HVS in the absence of antagonistic mechanisms. In contrast, we observed that PML, which was neither degraded nor redistributed after HVS infection, strongly restricted both wild-type HVS and virus with the ORF3 deletion. Thus, HVS may lack a factor that efficiently counteracts the repressive function of PML, which may foster latency as the outcome of infection.
authors.affiliation: Institut für Klinische und Molekulare Virologie, Universitätsklinikum, Friedrich Alexander Universität, Erlangen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Full
authors.forename: Nina
authors.initials: N
authors.lastname: Reuter
authors.forename: Katrin
authors.initials: K
authors.lastname: Zielke
authors.forename: Thomas
authors.initials: T
authors.lastname: Stamminger
authors.forename: Armin
authors.initials: A
authors.lastname: Ensser
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D006567:Herpesvirus 2, Saimiriine / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007109:Immunity; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D016366:Open Reading Frames; D011485:Protein Binding; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D001324:Autoantigens; C094297:CALCOCO2 protein, human; D009687:Nuclear Proteins; D014764:Viral Proteins; C066642:SP100 protein, human