Quantitative glycoproteomics reveals cellular substrate selectivity of the ER protein quality control sensors UGGT1 and UGGT2

Author:

Adams Benjamin M12ORCID,Canniff Nathan P12,Guay Kevin P12,Larsen Ida Signe Bohse34,Hebert Daniel N12ORCID

Affiliation:

1. Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, United States

2. Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, United States

3. Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

4. Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark

Abstract

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.

Funder

National Institute of General Medical Sciences

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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