New insights on the functional role of URG7 in the cellular response to ER stress. (30th May 2018)

• Record Type: Journal Article
• Authors: Armentano, Maria Francesca; Caterino, Marianna; Miglionico, Rocchina; Ostuni, Angela; Pace, Maria Carmela; Cozzolino, Flora; Monti, Maria; Milella, Luigi; Carmosino, Monica; Pucci, Piero; Bisaccia, Faustino
• Is Part Of: Biology of the cell. Volume 110:Number 7(2018)
• Page Start: 147
• Page End: 158
• Publication Date: 2018-05-30
• Subjects: Apoptosis -- ER stress -- PI3K/AKT -- UPR -- URG7; Cytology -- Periodicals; Electron microscopy -- Periodicals; 571.6
• DOI: 10.1111/boc.201800004
• Languages: English
• ISSNs: 0248-4900

Abstract

Abstract : Background information: Up‐regulated Gene clone 7 (URG7) is an ER resident protein, whose expression is up‐regulated in the presence of hepatitis B virus X antigen (HBxAg) during HBV infection. In virus‐infected hepatocytes, URG7 shows an anti‐apoptotic activity due to the PI3K/AKT signalling activation, does not seem to have tumorigenic properties, but it appears to promote the development and progression of fibrosis. However, the molecular mechanisms underlying URG7 activity remain largely unknown. Results: To shed light on URG7 activity, we first analysed its interactome in HepG2 transfected cells: this analysis suggests that URG7 could have a role in affecting protein synthesis, folding and promoting proteins degradation. Moreover, keeping into account its subcellular localisation in the ER and that several viral infections give rise to ER stress, a panel of experiments was performed to evaluate a putative role of URG7 in ER stress. Our main results demonstrate that in ER‐stressed cells URG7 is able to modulate the expression of Unfolded Protein Response (UPR) markers towards survival outcomes, up‐regulating GRP78 protein and down‐regulating the pro‐apoptotic protein CHOP. Furthermore, URG7 reduces the ER stress by decreasing the amount of unfolded proteins, by increasing both the total protein ubiquitination and the AKT activation and reducing Caspase 3 activation. Conclusions: All together these data suggest that URG7 plays a pivotal role as a reliever of ER stress‐induced apoptosis. Significance: This is the first characterisation of URG7 activity under ER stress conditions. The results presented here will help to hypothesise new strategies to counteract the antiapoptotic activity of URG7 in the context of the viral infection. Research article: URG7 is an ER resident protein, whose expression is up‐regulated during HBV infection. In ER‐stressed cells, URG7 is able to modulate the expression of UPR markers towards survival outcomes and to reduce the ER stress by decreasing the amount of unfolded proteins and by the PI3K/AKT pathway activation. All together these data suggest that URG7 plays a pivotal role as a reliever of ER stress‐induced apoptosis, suggesting new strategies to counteract its antiapoptotic activity in the context of the viral infection.