Regulation of EBNA1 protein stability and DNA replication activity by PLOD1 lysine hydroxylase.
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
28
03
2022
accepted:
15
05
2023
revised:
13
06
2023
medline:
15
6
2023
pubmed:
1
6
2023
entrez:
1
6
2023
Statut:
epublish
Résumé
Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus that is causally associated with various malignancies and autoimmune disease. Epstein-Barr Nuclear Antigen 1 (EBNA1) is the viral-encoded DNA binding protein required for viral episome maintenance and DNA replication during latent infection in proliferating cells. EBNA1 is known to be a highly stable protein, but the mechanisms regulating protein stability and how this may be linked to EBNA1 function is not fully understood. Proteomic analysis of EBNA1 revealed interaction with Procollagen Lysine-2 Oxoglutarate 5 Dioxygenase (PLOD) family of proteins. Depletion of PLOD1 by shRNA or inhibition with small molecule inhibitors 2,-2' dipyridyl resulted in the loss of EBNA1 protein levels, along with a selective growth inhibition of EBV-positive lymphoid cells. PLOD1 depletion also caused a loss of EBV episomes from latently infected cells and inhibited oriP-dependent DNA replication. Mass spectrometry identified EBNA1 peptides with lysine hydroxylation at K460 or K461. Mutation of K460, but not K461 abrogates EBNA1-driven DNA replication of oriP, but did not significantly affect EBNA1 DNA binding. Mutations in both K460 and K461 perturbed interactions with PLOD1, as well as decreased EBNA1 protein stability. These findings suggest that PLOD1 is a novel interaction partner of EBNA1 that regulates EBNA1 protein stability and function in viral plasmid replication, episome maintenance and host cell survival.
Identifiants
pubmed: 37262099
doi: 10.1371/journal.ppat.1010478
pii: PPATHOGENS-D-22-00560
pmc: PMC10263308
doi:
Substances chimiques
EBV-encoded nuclear antigen 1
O5GA75RST7
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
EC 1.14.11.4
Lysine
K3Z4F929H6
Epstein-Barr Virus Nuclear Antigens
0
PLOD1 protein, human
EC 1.14.11.4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1010478Subventions
Organisme : NIDCR NIH HHS
ID : R01 DE017336
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA093606
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009171
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA221838
Pays : United States
Informations de copyright
Copyright: © 2023 Dheekollu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
PL is a founder and advisor of Vironika, LLC and holds patents on a small molecule inhibitor of EBNA1. All other authors have no conflicts to disclose.
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