Glycoprotein folding and quality-control mechanisms in protein-folding diseases

Abstract

Biosynthesis of proteins – from translation to folding to export – encompasses a complex set of events that are exquisitely regulated and scrutinized to ensure the functional quality of the end products. Cells have evolved to capitalize on multiple post-translational modifications in addition to primary structure to indicate the folding status of nascent polypeptides to the chaperones and other proteins that assist in their folding and export. These modifications can also, in the case of irreversibly misfolded candidates, signal the need for dislocation and degradation. The current Review focuses on the glycoprotein quality-control (GQC) system that utilizes protein N-glycosylation and N-glycan trimming to direct nascent glycopolypeptides through the folding, export and dislocation pathways in the endoplasmic reticulum (ER). A diverse set of pathological conditions rooted in defective as well as over-vigilant ER quality-control systems have been identified, underlining its importance in human health and disease. We describe the GQC pathways and highlight disease and animal models that have been instrumental in clarifying our current understanding of these processes.

Impact of cell culture media additives on IgG glycosylation produced in Chinese hamster ovary cells

“…(Ferris, Kodali, & Kaufman, 2014;Lederkremer, 2009 (Trombetta, 2003;Tulsiani, Hubbard, Robbins, & Touster, 1982). (Ferris, Kodali, & Kaufman, 2014;Lederkremer, 2009 (Trombetta, 2003;Tulsiani, Hubbard, Robbins, & Touster, 1982).…”

Arsenic Triglutathione [As(GS)3] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23

“…Interestingly, reduced N-linked glycosylation of MRP1 has been reported in an oxaliplatin-selected ovarian carcinoma cell line relative to its parental cell line (Beretta et al, 2010). The sugar group content of glycosylation has been reported to differ for other N-glycosylated proteins between different cell and tissue types and during disease states (Fujimori-Arai et al, 1997;Peng et al, 2003;Fujikura et al, 2011;Bull et al, 2014;Ferris et al, 2014). Thus, it is possible that the composition of MRP1 glycosylation could vary between different healthy tissue types and different disease states, which in turn could alter MRP1 phosphorylation at Tyr920 and Ser921.…”

Beyond water homeostasis: Diverse functional roles of mammalian aquaporins

“…However, the plasma membrane localization of PC1 was almost completely abolished and PC1 was differentially glycosylated in the AQP11 -/-mice compared to AQP11 +/+ [165]. Glycosylation of some membrane proteins is a crucial step in protein folding and passage through the ER quality control system [166]. Other membrane proteins (AQP1 and PC2) were correctly glycosylated, suggesting that this was a PC1 specific effect.…”