Glucosidase and mannosidase inhibitors mediate increased secretion of mutant alpha 1 antitrypsin Z

It is now well known that the addition and trimming of oligosaccharide side chains during post-translational modification play an important role in de termining the fate of secretory, membrane, and lysosomal glycoproteins, Rec ent studies have suggested that trimming of oligosaccharide side chains als o plays a role in the degradation of misfolded glycoproteins as a part of t he quality control mechanism of the endoplasmic reticulum (ER), In this stu dy, we examined the effect of several inhibitors of carbohydrate processing on the fate of the misfolded secretory protein alpha 1 antitrypsin Z. Rete ntion of this misfolded glycoprotein in the ER of liver cells in the classi cal form of alpha 1 antitrypsin (alpha 1-AT) deficiency is associated with severe liver injury and hepatocellular carcinoma and lack of its secretion is associated with destructive lung disease/emphysema. The results show mar ked alterations in the fate of alpha 1 antitrypsin Z (alpha 1-ATZ), Indeed, one glucosidase inhibitor, castanospermine (CST), and two mannosidase inhi bitors, kifunensine (RIF) and deoxymannojirimycin (DMJ), mediate marked inc reases in secretion of alpha 1-ATZ by distinct mechanisms. The effects of t hese inhibitors on secretion have interesting implications for our understa nding of the quality control apparatus of the ER, These inhibitors may also constitute models for development of additional drugs for chemoprophylaxis of liver injury and emphysema in patients with alpha 1-AT deficiency.