Epigenetic factor siRNA screen during primary KSHV infection identifies novel host restriction factors for the lytic cycle of KSHV

English version

Autoři: Nenavath Gopal Naik ^aff001; Thomas Hong Nguyen ^aff001; Lauren Roberts ^aff001; Luke Todd Fischer ^aff001; Katherine Glickman ^aff001; Gavin Golas ^aff001; Bernadett Papp ^aff001; Zsolt Toth ^aff001
Působiště autorů: Department of Oral Biology, University of Florida College of Dentistry, 1395 Center Drive, Gainesville, FL, United States of America ^aff001; UF Genetics Institute, Gainesville, FL, United States of America ^aff002; UF Health Cancer Center, Gainesville, FL, United States of America ^aff003; UF Informatics Institute, Gainesville, FL, United States of America ^aff004
Vyšlo v časopise: Epigenetic factor siRNA screen during primary KSHV infection identifies novel host restriction factors for the lytic cycle of KSHV. PLoS Pathog 16(1): e32767. doi:10.1371/journal.ppat.1008268
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008268

Souhrn

Establishment of viral latency is not only essential for lifelong Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, but it is also a prerequisite of viral tumorigenesis. The latent viral DNA has a complex chromatin structure, which is established in a stepwise manner regulated by host epigenetic factors during de novo infection. However, despite the importance of viral latency in KSHV pathogenesis, we still have limited information about the repertoire of epigenetic factors that are critical for the establishment and maintenance of KSHV latency. Therefore, the goal of this study was to identify host epigenetic factors that suppress lytic KSHV genes during primary viral infection, which would indicate their role in latency establishment. We performed an siRNA screen targeting 392 host epigenetic factors during primary infection and analyzed which ones affect the expression of the viral replication and transcription activator (RTA) and/or the latency-associated nuclear antigen (LANA), which are viral genes essential for lytic replication and latency, respectively. As a result, we identified the Nucleosome Remodeling and Deacetylase (NuRD) complex, Tip60 and Tip60-associated co-repressors, and the histone demethylase KDM2B as repressors of KSHV lytic genes during both de novo infection and the maintenance of viral latency. Furthermore, we showed that KDM2B rapidly binds to the incoming viral DNA as early as 8 hpi, and can limit the enrichment of activating histone marks on the RTA promoter favoring the downregulation of RTA expression even prior to the polycomb proteins-regulated heterochromatin establishment on the viral genome. Strikingly, KDM2B can also suppress viral gene expression and replication during lytic infection of primary gingival epithelial cells, revealing that KDM2B can act as a host restriction factor of the lytic cycle of KSHV during both latent and lytic infections in multiple different cell types.

Klíčová slova:

Epigenetics – Gene expression – Histones – Kaposi's sarcoma-associated herpesvirus – Small interfering RNAs – Viral gene expression – Viral persistence and latency – Virus effects on host gene expression

Zdroje

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