Epigenetic factor siRNA screen during primary KSHV infection identifies novel host restriction factors for the lytic cycle of KSHV.
Antigens, Viral
/ genetics
Epigenesis, Genetic
F-Box Proteins
/ genetics
Gene Expression Regulation, Viral
Herpesviridae Infections
/ genetics
Herpesvirus 8, Human
/ genetics
Humans
Immediate-Early Proteins
/ genetics
Jumonji Domain-Containing Histone Demethylases
/ genetics
Lysine Acetyltransferase 5
/ genetics
Nuclear Proteins
/ genetics
RNA, Small Interfering
/ genetics
Trans-Activators
/ genetics
Virus Latency
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
16
08
2019
accepted:
09
12
2019
revised:
23
01
2020
pubmed:
11
1
2020
medline:
6
5
2020
entrez:
11
1
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31923286
doi: 10.1371/journal.ppat.1008268
pii: PPATHOGENS-D-19-01531
pmc: PMC6977772
doi:
Substances chimiques
Antigens, Viral
0
F-Box Proteins
0
Immediate-Early Proteins
0
Nuclear Proteins
0
RNA, Small Interfering
0
Rta protein, Human herpesvirus 8
0
Trans-Activators
0
latency-associated nuclear antigen
0
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
KDM2A protein, human
EC 1.14.11.27
KAT5 protein, human
EC 2.3.1.48
Lysine Acetyltransferase 5
EC 2.3.1.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008268Subventions
Organisme : NIAID NIH HHS
ID : R01 AI132554
Pays : United States
Organisme : NIDCR NIH HHS
ID : R03 DE025562
Pays : United States
Organisme : NIDCR NIH HHS
ID : R03 DE028029
Pays : United States
Organisme : NIDCR NIH HHS
ID : T90 DE021990
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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