MmuPV1 E7's interaction with PTPN14 delays Epithelial differentiation and contributes to virus-induced skin disease.
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
12
07
2022
accepted:
17
02
2023
medline:
12
4
2023
entrez:
10
4
2023
pubmed:
11
4
2023
Statut:
epublish
Résumé
Human papillomaviruses (HPVs) contribute to approximately 5% of all human cancers. Species-specific barriers limit the ability to study HPV pathogenesis in animal models. Murine papillomavirus (MmuPV1) provides a powerful tool to study the roles of papillomavirus genes in pathogenesis arising from a natural infection. We previously identified Protein Tyrosine Phosphatase Non-Receptor Type 14 (PTPN14), a tumor suppressor targeted by HPV E7 proteins, as a putative cellular target of MmuPV1 E7. Here, we confirmed the MmuPV1 E7-PTPN14 interaction. Based on the published structure of the HPV18 E7/PTPN14 complex, we generated a MmuPV1 E7 mutant, E7K81S, that was defective for binding PTPN14. Wild-type (WT) and E7K81S mutant viral genomes replicated as extrachromosomal circular DNAs to comparable levels in mouse keratinocytes. E7K81S mutant virus (E7K81S MmuPV1) was generated and used to infect FoxN/Nude mice. E7K81S MmuPV1 caused neoplastic lesions at a frequency similar to that of WT MmuPV1, but the lesions arose later and were smaller than WT-induced lesions. The E7K81S MmuPV1-induced lesions also had a trend towards a less severe grade of neoplastic disease. In the lesions, E7K81S MmuPV1 supported the late (productive) stage of the viral life cycle and promoted E2F activity and cellular DNA synthesis in suprabasal epithelial cells to similar degrees as WT MmuPV1. There was a similar frequency of lateral spread of infections among mice infected with E7K81S or WT MmuPV1. Compared to WT MmuPV1-induced lesions, E7K81S MmuPV1-induced lesions had a significant expansion of cells expressing differentiation markers, Keratin 10 and Involucrin. We conclude that an intact PTPN14 binding site is necessary for MmuPV1 E7's ability to contribute to papillomavirus-induced pathogenesis and this correlates with MmuPV1 E7 causing a delay in epithelial differentiation, which is a hallmark of papillomavirus-induced neoplasia.
Identifiants
pubmed: 37036883
doi: 10.1371/journal.ppat.1011215
pii: PPATHOGENS-D-22-01209
pmc: PMC10085053
doi:
Substances chimiques
Oncogene Proteins, Viral
0
Papillomavirus E7 Proteins
0
Protein Tyrosine Phosphatases, Non-Receptor
EC 3.1.3.48
PTPN14 protein, mouse
EC 3.1.3.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1011215Subventions
Organisme : NCI NIH HHS
ID : P01 CA022443
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA254019
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA228543
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI148431
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA278595
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA210807
Pays : United States
Informations de copyright
Copyright: © 2023 Romero-Masters 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
The authors have declared that no competing interests exist.
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