Helenius and colleagues proposed over twenty-years ago a paradigm-shifting model for how chaperone binding in the endoplasmic reticulum was mediated and controlled for a new type of molecular chaperone- the carbohydrate binding chaperones, calnexin and calreticulin. While the originally established basics for this lectin chaperone binding cycle holds true today, there has been a number of important advances that have expanded our understanding of its mechanisms of action, role in protein homeostasis, and its connection to disease states that are highlighted in this review.

The site of protein folding and maturation for the majority of proteins that are secreted, localized to the plasma membrane or targeted to endomembrane compartments is the endoplasmic reticulum (ER). It is essential that proteins targeted to the ER are properly folded in order to carry out their function, as well as maintain protein homeostasis, as accumulation of misfolded proteins could lead to the formation of cytotoxic aggregates. Because protein folding is an error-prone process, the ER contains protein quality control networks that act to optimize proper folding and trafficking of client proteins. If a protein is unable to reach its native state, it is targeted for ER retention and subsequent degradation. The protein quality control networks of the ER that oversee this evaluation or interrogation process that decides the fate of maturing nascent chains is comprised of three general types of families: the classical chaperones, the carbohydrate-dependent system, and the thiol-dependent system. The cooperative action of these families promotes protein quality control and protein homeostasis in the ER. This review will describe the families of the ER protein quality control network and discuss the functions of individual members.

UDP-glucose:glycoprotein glucosyltransferase (UGGT) 1 and 2 are central hubs in the chaperone network of the endoplasmic reticulum (ER), acting as gatekeepers to the early secretory pathway, yet little is known about their cellular clients. These two quality control sensors control lectin chaperone binding and glycoprotein egress from the ER. A quantitative glycoproteomics strategy was deployed to identify cellular substrates of the UGGTs at endogenous levels in CRISPR-edited HEK293 cells. The 71 UGGT substrates identified were mainly large multidomain and heavily glycosylated proteins when compared to the general N-glycoproteome. UGGT1 was the dominant glucosyltransferase with a preference toward large plasma membrane proteins whereas UGGT2 favored the modification of smaller, soluble lysosomal proteins. This study sheds light on differential specificities and roles of UGGT1 and UGGT2 and provides insight into the cellular reliance on the carbohydrate-dependent chaperone system to facilitate proper folding and maturation of the cellular N-glycoproteome.

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UDP-glucose: glycoprotein glucosyltransferase (UGGT) 1 and 2 are central hubs in the chaperone network of the endoplasmic reticulum (ER), acting as gatekeepers to the early secretory pathway yet little is known about their cellular clients. These two quality control sensors control lectin chaperone binding and glycoprotein egress from ER. A quantitative glycoproteomics strategy was deployed to identify cellular substrates of the UGGTs at endogenous levels in CRISPR-edited HEK293 cells. The seventy-one UGGT substrates identified were mainly large multidomain and heavily glycosylated proteins when compared to the general N-glycome. UGGT1 was the dominant glucosyltransferase with a preference towards large plasma membrane proteins whereas UGGT2 favored the modification of smaller, soluble lysosomal proteins. This study sheds light on differential specificities and roles of UGGT1 and UGGT2 and provides insight into the cellular reliance on carbohydrate-dependent chaperone intervention