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Author ORCID Identifier
Open Access Dissertation
Doctor of Philosophy (PhD)
Molecular and Cellular Biology
Year Degree Awarded
Month Degree Awarded
Biochemistry | Molecular Biology
The UDP-glucose:glycoprotein glucosyltransferase 1 (UGT1) is a central quality control factor in the Endoplasmic Reticulum (ER). It surveys the folding status of proteins in the ER and redirects them, via its reglucosylation activity, to bind to the ER carbohydrate binding (lectin) chaperones calreticulin (CRT) and calnexin (CNX). However, the cellular mechanism of UGT1 is not completely understood. Using a cell based reglucosylation assay, we found that UGT1 reglucosylated proteins that eventually fold. This modification was transient and resulted in delay of protein trafficking in the secretory pathway and prolonged binding to lectin chaperones in the ER. In addition, terminally misfolded substrates, disease associated mutants or proteins with reduced disulfides were reglucosylated by UGT1. Yet, this reglucosylation, despite being efficient and persistent, did not affect their degradation by the ER-associated degradation pathway. This suggested that degradation occurred independently of the glucose containing branch on the substrate’s glycan. Further investigation showed that trimming mannose residues of the substrate’s glycan is responsible for terminating the substrate reglucosylation by UGT1 in the ER. Moreover, our preliminary data suggests that the free cysteines of the substrate might aid in its recognition and persistent reglucosylation by UGT1. Thus, our strategy unraveled new details of the role of UGT1 in ER quality control that further highlight its importance in protein maturation.
Tannous, Abla, "NEW INSIGHTS INTO THE ROLE OF THE UDP-GLUCOSE: GLYCOPROTEIN GLUCOSYLTRANSFERASE 1 IN THE ENDOPLASMIC RETICULUM QUALITY CONTROL" (2015). Doctoral Dissertations. 452.