Expression of Sep15, a thioredoxin‐like selenoprotein, is induced in response to accumulation of unfolded proteins in the endoplasmic reticulum

Abstract

The process of protein folding in the endoplasmic reticulum (ER) of mammalian cells is assisted by an extensive network of molecular chaperones and thiol-disulfide oxidoreductases, enzymes that catalyze formation of disulfide bonds. Recently, a novel selenocysteine-containing oxidoreductase, Sep15, has been reported to reside in the ER lumen, and a role in disulfide bond formation and quality control in the ER has been proposed for this selenoprotein. In order to address the possible role of Sep15 in protein folding, we analyzed whether expression of Sep15 is increased in response to accumulation of unfolded proteins within the ER. Herein, we demonstrate that Sep15 expression is increased in NIH3T3 cells in response to ER stress caused by tunicamycin and brefeldin A, whereas DTT stimulates specific degradation of Sep15 by proteasomes. We also tested whether Sep15 deficiency leads to accumulation of unfolded proteins and cause ER stress. Indeed, decreased levels of Sep15 caused by selenium deficiency combined with down-regulation of a Sep15 homolog, SelM, by RNA interference activated unfolded protein response. Together, these data further support the role of Sep15 in protein folding and suggest that its function may be compensated by SelM.