The glucose-regulated protein GRP94 interacts avidly in the endoplasmic reticulum with sucrase-isomaltase isoforms that are associated with congenital sucraseisomaltase deficiency

Int J Biol Macromol. 2021 Sep 1;186:237-243. doi: 10.1016/j.ijbiomac.2021.07.030.

PMID: 34242650

Abdullah Hoter, Hassan Y Naim

Highlights: In this study, an interaction between glucose-regulated protein GRP94 and sucrase-isomaltase (SI) was demonstrated. The interaction of GRP94 with SI and regulation of its folding, suggests that GRP94 may play a role in maintaining intestinal homeostasis.

Abstract

Background: The glucose-regulated protein GRP94 is a molecular chaperone that is located in the endoplasmic reticulum (ER).

Methods and results: In this paper, an interaction between GRP94 and sucrase-isomaltase (SI), the most prominent disaccharidase of the small intestine was demonstrated in pull down experiments. GRP94 binds to SI exclusively via its mannose-rich form compatible with an interaction occurring in the ER. Researchers also examined the interaction GRP94 to a panel of SI mutants that are associated with congenital sucraseisomaltase deficiency (CSID). These mutants exhibited more efficient binding to GRP94 than wild type SI underlining a specific role of this chaperone in the quality control in the ER. In view of the hypoxic milieu of the intestine the interaction of GRP94 to SI and its mutants in cell culture under hypoxic conditions was probed and a substantial increase in the binding of GRP94 to the SI mutants was observed.

Conclusion: The interaction of GRP94 to the major carbohydrate digesting enzyme and regulating its folding as well as retaining SI mutants in the ER points to a potential role of GRP94 in maintenance of intestinal homeostasis by chaperoning and stabilizing SI.

Keywords: ER stress, GRP94, Hypoxia, Intestinal enzymes, Molecular chaperones, Protein quality control, Sucrase-isomaltase