Modulation of ATF6-modulated unfolded protein response induction by human papillomavirus E6 oncoprotein

Abstract

In ER stress conditions, the levels of molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) are controlled by a transcriptional induction process termed the unfolded protein response (UPR). ATF6, a member of the leucine zipper transcription factor family, can constitutively induce the promoter of glucose regulated protein genes through activation of the ER stress element (ERSE). When ER stress is induced, ATF6 is activated by protease-mediated cleavage and activates ERSE-mediated transcription to survive under ER stress conditions that cause continuous accumulation of unfolded proteins in the ER. During viral infection, host cell must be protected from ER stress so that virus can maintain stable viral life cycle. Because if cells are not able to endure ER stress, they set up a signal transduction pathway toward apoptosis, virus should take necessary action to keep host cells alive. The human papillomavirus E6 is recognized as potent viral oncogene and is associated with malignant tumor formation. In this present study, we deciphered whether UPR can be induced by viral infection and can be modulated by expression of viral oncogene. E6 activated ERSE specific promoter (Grp78 promoter) in transient transfection assay. In contrast, other HPV genes such as E2 and E7 did not activate Grp78 promoter. In addition, E6 of high-risk, especially HPV16 E6 augmented Grp78 promoter activity strongly while E6 of low-risk group, if any, activated it slightly. Using biochemical approaches, E6 did bind to ATF6 in vitro and in vivo, and the bZIP DNA binding region of ATF6 is significant for interaction with E6. In addition, transformation defective mutant HPV-16 E6 did not activate Grp78 promoter, indicating that structural integrity of E6 is important for its oncogenic potential and the ATF6-mediated UPR induction. From these data, we conclude that E6 activates UPR induction and protein-protein interaction between E6 and ATF6 may be significant for maintaini...