An intrinsic mechanism of secreted protein aging and turnover.
The composition and functions of the secreted proteome are controlled by the life spans of different proteins. However, unlike intracellular protein fate, intrinsic factors determining secreted protein aging and turnover have not been identified and characterized. Almost all secreted proteins are posttranslationally modified with the covalent attachment of N-glycans. We have discovered an intrinsic mechanism of secreted protein aging and turnover linked to the stepwise elimination of saccharides attached to the termini of N-glycans. Endogenous glycosidases, including neuraminidase 1 (Neu1), neuraminidase 3 (Neu3), beta-galactosidase 1 (Glb1), and hexosaminidase B (HexB), possess hydrolytic activities that temporally remodel N-glycan structures, progressively exposing different saccharides with increased protein age. Subsequently, endocytic lectins with distinct binding specificities, including the Ashwell-Morell receptor, integrin αM, and macrophage mannose receptor, are engaged in N-glycan ligand recognition and the turnover of secreted proteins. Glycosidase inhibition and lectin deficiencies increased protein life spans and abundance, and the basal rate of N-glycan remodeling varied among distinct proteins, accounting for differences in their life spans. This intrinsic multifactorial mechanism of secreted protein aging and turnover contributes to health and the outcomes of disease.
Center for Nanomedicine, University of California, Santa Barbara, CA 93106; Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037;
Won Ho
WH
Yang
Center for Nanomedicine, University of California, Santa Barbara, CA 93106; Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037;
Peter V
PV
Aziz
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106.
Douglas M
DM
Heithoff
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106.
Michael J
MJ
Mahan
Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037;
Jeffrey W
JW
Smith
Center for Nanomedicine, University of California, Santa Barbara, CA 93106; Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106 jmarth@sbpdiscovery.org.
Jamey D
JD
Marth
D006031:Glycosylation; D011134:Polysaccharides / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism*
D011134:Polysaccharides; D011506:Proteins
glycosidase; glycosylation; homeostasis; lectin; protein