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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-03-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006262&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849467438038515712 |
|---|---|
| author | Domenico Mattoscio Chiara Casadio Claudia Miccolo Fausto Maffini Andrea Raimondi Carlo Tacchetti Tarik Gheit Marta Tagliabue Viviana E Galimberti Francesca De Lorenzi Michael Pawlita Fausto Chiesa Mohssen Ansarin Massimo Tommasino Susanna Chiocca |
| author_facet | Domenico Mattoscio Chiara Casadio Claudia Miccolo Fausto Maffini Andrea Raimondi Carlo Tacchetti Tarik Gheit Marta Tagliabue Viviana E Galimberti Francesca De Lorenzi Michael Pawlita Fausto Chiesa Mohssen Ansarin Massimo Tommasino Susanna Chiocca |
| author_sort | Domenico Mattoscio |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4db8a8c3ffdd42f3b3e247e424fd03ed |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2017-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-4db8a8c3ffdd42f3b3e247e424fd03ed2025-08-20T03:26:14ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-03-01133e100626210.1371/journal.ppat.1006262Autophagy regulates UBC9 levels during viral-mediated tumorigenesis.Domenico MattoscioChiara CasadioClaudia MiccoloFausto MaffiniAndrea RaimondiCarlo TacchettiTarik GheitMarta TagliabueViviana E GalimbertiFrancesca De LorenziMichael PawlitaFausto ChiesaMohssen AnsarinMassimo TommasinoSusanna ChioccaUBC9, 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006262&type=printable |
| spellingShingle | Domenico Mattoscio Chiara Casadio Claudia Miccolo Fausto Maffini Andrea Raimondi Carlo Tacchetti Tarik Gheit Marta Tagliabue Viviana E Galimberti Francesca De Lorenzi Michael Pawlita Fausto Chiesa Mohssen Ansarin Massimo Tommasino Susanna Chiocca Autophagy regulates UBC9 levels during viral-mediated tumorigenesis. PLoS Pathogens |
| title | Autophagy regulates UBC9 levels during viral-mediated tumorigenesis. |
| title_full | Autophagy regulates UBC9 levels during viral-mediated tumorigenesis. |
| title_fullStr | Autophagy regulates UBC9 levels during viral-mediated tumorigenesis. |
| title_full_unstemmed | Autophagy regulates UBC9 levels during viral-mediated tumorigenesis. |
| title_short | Autophagy regulates UBC9 levels during viral-mediated tumorigenesis. |
| title_sort | autophagy regulates ubc9 levels during viral mediated tumorigenesis |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006262&type=printable |
| work_keys_str_mv | AT domenicomattoscio autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT chiaracasadio autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT claudiamiccolo autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT faustomaffini autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT andrearaimondi autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT carlotacchetti autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT tarikgheit autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT martatagliabue autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT vivianaegalimberti autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT francescadelorenzi autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT michaelpawlita autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT faustochiesa autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT mohssenansarin autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT massimotommasino autophagyregulatesubc9levelsduringviralmediatedtumorigenesis AT susannachiocca autophagyregulatesubc9levelsduringviralmediatedtumorigenesis |