New insights on the functional role of URG7 in the cellular response to ER stress.

BACKGROUND INFORMATION: Up-regulated Gene clone 7 (URG7) is an ER resident protein, whose expression is upregulated 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 signaling 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 analyzed 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 localization 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 toward survival outcomes, upregulating GRP78 protein and downregulating 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 characterization of URG7 activity under ER stress conditions. The results presented here will help to hypothesize new strategies to counteract the antiapoptotic activity of URG7 in the context of the viral infection. This article is protected by copyright. All rights reserved.