Gammaherpesvirale Tegumentproteine - wichtige Effektoren viraler Infektionen
Zusammenfassung der Projektergebnisse
The Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) in humans, and herpesvirus saimiri (HVS) and rhesus monkey rhadinovirus (RRV) in nonhuman primates, belong to the Gammaherpesvirus subfamily. They share many key biological features and infect cells of both human and primate origin. Nuclear domain 10 (ND10) components like PML, SP100 and ATRX restrict herpesviral infection; herpesviruses antagonize this restriction by a variety of strategies, including degradation or relocalization of ND10 and other proteins. Among the cellular interaction partners of the tegument proteins KSHV ORF75 and EBV BNRF1 are several host proteins containing Structural Maintenance of Chromosomes (SMC) domains. Expression of ORF75 or BNRF1 depleted the SMC protein or relocated it to ND10 domains. First, the SMCHD1 protein was identified as a target of KSHV ORF75. SMCHD1 is a known epigenetic regulator of the DUX4 gene. We found that induction of DUX4 transcriptional targets is common after herpesvirus infection and also critical for herpesvirus replication, making DUX4 a potential drug target. Since SMCHD1 is also a known tumor suppressor, involved in heterochromatin formation and DNA repair, we further studied the DNA damage response (DDR) in cells transfected with the viral tegument protein ORF75 or its homologs, after inflicting DNA damage with bleomycin and additional drugs. Several DDR markers, namely phosphorylation of DNA-PKcs, ATM, gH2AX, p53, and damage induced 53BP1 foci, were reduced in cells expressing KSHV ORF75 and its homologs. Biologically, the inhibition of the DRR by tegument proteins could prevent the detection of the incoming viral genome, which due to its linear structure with free DNA ends resembles damaged DNA. While activation of DDR is a longer known feature of viral lytic replication, our data indicates that inhibition of DDR and depletion of the SMC5/6 complex may take place in the early phase of infection and latency establishment. SMC5/6 has central roles in the control of episomal transcription, relieves transcriptional stress and senses and prevents DNA damage. When DDR inhibition occurs at the same time as SMC5/6 depletion, this may be a critical vulnerability and it could contribute to KSHV and EBV oncogenesis.
Projektbezogene Publikationen (Auswahl)
- Centrosomal protein TRIM43 restricts herpesvirus infection by regulating nuclear lamina integrity. Nat Microbiol 4, 164-176 (2019)
Full, F. et al.
(Siehe online unter https://doi.org/10.1038/s41564-018-0285-5) - Early Nuclear Events after Herpesviral Infection. J Clin Med 8 (2019)
Full, F. & Ensser, A.
(Siehe online unter https://doi.org/10.3390/jcm8091408) - (2021) Herpesviral induction of germline transcription factor DUX4 is critical for viral gene expression. Preprint bioRxiv
Walter S, Franke V, Drayman N, Wyler E, Tay S, Landthaler M, Akalin A, Ensser A, & Full F
(Siehe online unter https://doi.org/10.1101/2021.03.24.436599)
