Autophagy regulates UBC9 levels during viral-mediated tumorigenesis

UBC9, the sole E2-conjugating enzyme required for SUMOylation, is a key regulator of essential cellular functions and, as such, is frequently altered in cancers. Along these lines, we recently reported that its expression gradually increases during early stages of human papillomavirus (HPV)-mediated...

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Vydáno v:	PLoS pathogens Ročník 13; číslo 3; s. e1006262
Hlavní autoři:	Mattoscio, Domenico, Casadio, Chiara, Miccolo, Claudia, Maffini, Fausto, Raimondi, Andrea, Tacchetti, Carlo, Gheit, Tarik, Tagliabue, Marta, Galimberti, Viviana E., De Lorenzi, Francesca, Pawlita, Michael, Chiesa, Fausto, Ansarin, Mohssen, Tommasino, Massimo, Chiocca, Susanna
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 01.03.2017 Public Library of Science (PLoS)
Témata:	Apoptosis Autophagy Autophagy (Cytology) Autophagy - physiology Biology and life sciences Brain cancer Carcinogens Care and treatment Cell cycle Cell death Cell Transformation, Neoplastic Cell Transformation, Viral - physiology Cellular proteins Cervical cancer Development and progression Enzymes Female Flow Cytometry Genetic aspects Genetic transformation Head Head & neck cancer Head and neck Health aspects Human papillomavirus Humans Immunoblotting Immunohistochemistry Infections Keratinocytes Lesions Medical research Medicine and Health Sciences Microscopy, Confocal Oncogene Proteins, Viral Oncology Otolaryngology p53 Protein Papillomaviridae - metabolism Papillomavirus infections Papillomavirus Infections - metabolism Papillomavirus Infections - pathology Pathology Phagocytosis Pharmacology Polymerase Chain Reaction Proteins Research and Analysis Methods Rodents SUMO protein Surgery Tissues Transduction, Genetic Transfection Transformation Tumorigenesis Ubiquitin-Conjugating Enzyme UBC9 Ubiquitin-Conjugating Enzymes - metabolism Viruses
ISSN:	1553-7374, 1553-7366, 1553-7374
On-line přístup:	Získat plný text
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Popis
Shrnutí:	UBC9, the sole E2-conjugating enzyme required for SUMOylation, is a key regulator of essential cellular functions and, as such, is frequently altered in cancers. Along these lines, we recently reported that its expression gradually increases during early stages of human papillomavirus (HPV)-mediated cervical lesions transformation. However, a better understanding of how UBC9 is exploited by transforming viral oncoproteins is still needed. In the present study, we show that in human samples HPV drives UBC9 up-regulation also in very early steps of head and neck tumorigenesis, pointing to the important role for UBC9 in the HPV-mediated carcinogenic program. Moreover, using HPV-infected pre-cancerous tissues and primary human keratinocytes as the natural host of the virus, we investigate the pathological meaning and the cellular mechanisms responsible for UBC9 de-regulation in an oncoviral context. Our results show that UBC9 overexpression is promoted by transforming viral proteins to increase host cells' resistance to apoptosis. In addition, ultrastuctural, pharmacological and genetic approaches crucially unveil that UBC9 is physiologically targeted by autophagy in human cells. However, the presence of HPV E6/E7 oncoproteins negatively impacts the autophagic process through selective inhibition of autophagosome-lysosome fusion, finally leading to p53 dependent UBC9 accumulation during viral-induced cellular transformation. Therefore, our study elucidates how UBC9 is manipulated by HPV oncoproteins, details the physiological mechanism by which UBC9 is degraded in cells, and identifies how HPV E6/E7 impact on autophagy. These findings point to UBC9 and autophagy as novel hallmarks of HPV oncogenesis, and open innovative avenues towards the treatment of HPV-related malignancies.
Bibliografie:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 MP received research funding from cooperation contracts from the DKFZ with Roche and Qiagen. He is inventor and receives royalties on a patent held by DKFZ in the field of molecular diagnostics for infectious disease. Conceptualization: DM SC.Formal analysis: DM SC.Funding acquisition: FC MP MTo SC.Investigation: DM CC CM FM AR CT TG MP SC.Methodology: DM SC.Project administration: SC.Resources: MTa VEG FDL FC MA SC.Supervision: SC.Validation: DM CM SC.Visualization: DM CC CM FM SC.Writing – original draft: DM SC.Writing – review & editing: DM MTo SC.
ISSN:	1553-7374 1553-7366 1553-7374
DOI:	10.1371/journal.ppat.1006262