Felis catus papillomavirus type-2 E6 binds to E6AP, promotes E6AP/p53 binding and enhances p53 proteasomal degradation

E6 from high risk human papillomaviruses (HR HPVs) promotes ubiquitination and degradation of p53 tumour suppressor by mediating its binding to ubiquitin ligase E6AP in a ternary complex, contributing to cell transformation in cervical cancer. We have previously shown that Felis catus papillomavirus...

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Bibliographic Details
Published in:Scientific reports 2018-12, Vol.8 (1), p.17529-11, Article 17529
Main Authors: Altamura, Gennaro, Power, Karen, Martano, Manuela, degli Uberti, Barbara, Galiero, Giorgio, De Luca, Giovanna, Maiolino, Paola, Borzacchiello, Giuseppe
Format: Article
Language:English
Subjects:
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Animal models
Cervical cancer
Cervix
Down-regulation
Felis catus
Genetic transformation
Human papillomavirus
Humanities and Social Sciences
Kinases
Molecular modelling
mRNA
multidisciplinary
p53 Protein
Papillomaviridae
Proteasomes
Proteins
Science
Science (multidisciplinary)
Squamous cell carcinoma
Tumors
Ubiquitin
Ubiquitin-protein ligase
Ubiquitination
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Summary:E6 from high risk human papillomaviruses (HR HPVs) promotes ubiquitination and degradation of p53 tumour suppressor by mediating its binding to ubiquitin ligase E6AP in a ternary complex, contributing to cell transformation in cervical cancer. We have previously shown that Felis catus papillomavirus type −2 (FcaPV-2) E6 is expressed in feline squamous cell carcinoma (SCC) and displays the ability to bind p53 and decrease its protein levels in transfected CRFK cells. However, the mechanism of p53 downregulation has not yet been characterized. Here we show that FcaPV-2 E6 bound to E6AP, which in turn was bound by p53 exclusively in cells expressing the viral oncoprotein (CRFKE6). Furthermore, p53 was highly poly-ubiquitinated and underwent accumulation upon E6AP gene knockdown in CRFKE6. Half-life experiments and proteasome inhibition treatments indicated that down-regulation of p53 protein in CRFKE6 was due to accelerated proteasomal degradation. E6AP/p53 binding was also demonstrated in two feline SCC cell lines expressing FcaPV-2 E6, where p53 protein levels and poly-ubiquitination degree were proportional to E6 mRNA levels. The data obtained in both artificial and spontaneous in vitro models suggest that FcaPV-2 E6 degrades p53 through a molecular mechanism similar to HR HPVs, possibly contributing to the development of feline SCC.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-35723-7