Autophagy regulates UBC9 levels during viral-mediated tumorigenesis

Abstract

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.

Recent Highlights: Onco Viral Exploitation of the SUMO System

“…Notably, similar results were also found in human samples during the natural evolution of cervical and oropharyngeal cancer (Mattoscio et al, , 2017, underlining the importance of SUMO alterations during HPV transformation. Mechanistically, HPV16 E6/E7 prevents the autophagy-dependent UBC9 degradation obstructing the final step of autophagic pathway in E6/p53-dependent manner (Mattoscio et al, 2017(Mattoscio et al, , 2018. The resulting increased UBC9 level confers apoptosis resistance to the infected keratinocyte (Mattoscio et al, 2017), thus extending HPV persistence in the host and triggering cellular transformation.…”

“…Among these, clever strategies are adopted by HPV oncoproteins to hijack SUMO during infection and tumorigenesis. HPV16 E6 and E7 overexpression in the natural host of the virus, primary human keratinocytes, significantly increases the accumulation of UBC9 and SUMO1-conjugated species (Mattoscio et al, 2017). Notably, similar results were also found in human samples during the natural evolution of cervical and oropharyngeal cancer (Mattoscio et al, , 2017, underlining the importance of SUMO alterations during HPV transformation.…”

“…HPV16 E6 and E7 overexpression in the natural host of the virus, primary human keratinocytes, significantly increases the accumulation of UBC9 and SUMO1-conjugated species (Mattoscio et al, 2017). Notably, similar results were also found in human samples during the natural evolution of cervical and oropharyngeal cancer (Mattoscio et al, , 2017, underlining the importance of SUMO alterations during HPV transformation. Mechanistically, HPV16 E6/E7 prevents the autophagy-dependent UBC9 degradation obstructing the final step of autophagic pathway in E6/p53-dependent manner (Mattoscio et al, 2017(Mattoscio et al, , 2018.…”

“…Mechanistically, HPV16 E6/E7 prevents the autophagy-dependent UBC9 degradation obstructing the final step of autophagic pathway in E6/p53-dependent manner (Mattoscio et al, 2017(Mattoscio et al, , 2018. The resulting increased UBC9 level confers apoptosis resistance to the infected keratinocyte (Mattoscio et al, 2017), thus extending HPV persistence in the host and triggering cellular transformation. However, this E6-mediated UBC9 accumulation seems to be a cell-specific mechanism dependent on the cellular background of analysed cells.…”

Exosomes, the message transporters in vascular calcification

“…It is believed that small ubiquitin‐like modifier (SUMOylation) of hnRNPA2/B1 promotes miRs loading into exosomes . In addition, Ubc9, the E2‐conjugating enzymes mediating SUMOylation, is degraded in autophagy procession . Thus, autophagic flux partially decreases exosomes secretion and miRs loading into exosomes, which might interfere with mineral deposition and osteogenic phenotype transition.…”