Attenuation of unfolded protein response and apoptosis by mReg2 induced GRP78 in mouse insulinoma cells

• mReg2 inhibits ER stress-induced unfolded protein response in MIN6 cells.
• mReg2 increases basal expression of GRP78 via Akt–mTORC1 signaling axis.
• mReg2 attenuates ER stress-induced apoptosis.
• si-RNA mediated knockdown of GRP78 blunts the protective effect of mReg2.

Murine regenerating (mReg) genes have been implicated in preserving islet cell biology. Expanding on our previous work showing that overexpression of mReg2 protects MIN6 insulinoma cells against streptozotocin-induced apoptosis, we now demonstrate that mReg2 induces glucose-regulated peptide 78 (GRP78) expression via the Akt–mTORC1 axis and protects MIN6 cells against ER stress induced by thapsigargin and glucolipotoxicity. Activation of mTORC1 activity results from both mReg2-induced increased mTOR phosphorylation as well as increased expression of Raptor and GβL. Inhibition of Akt and mTORC1 blunted the ability of mReg2 to induce GRP78 and attenuate unfolded protein response (UPR). Knockdown of GRP78 sensitized the cells overexpressing mReg2 to UPR without affecting its ability to activate Akt–mTORC1 signaling. Induced expression of mReg2 may protect insulin producing cells from ER stress in diabetes.