Title | An intrinsic mechanism of secreted protein aging and turnover. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Yang WHo, Aziz PV, Heithoff DM, Mahan MJ, Smith JW, Marth JD |
Journal | Proc Natl Acad Sci U S A |
Volume | 112 |
Issue | 44 |
Pagination | 13657-62 |
Date Published | 2015 Nov 3 |
ISSN | 1091-6490 |
Abstract | 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. |
DOI | 10.1073/pnas.1515464112 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 26489654 |
PubMed Central ID | PMC4640737 |
Grant List | DK14842 / DK / NIDDK NIH HHS / United States GM100192 / GM / NIGMS NIH HHS / United States HL125352 / HL / NHLBI NIH HHS / United States R01 DK048247 / DK / NIDDK NIH HHS / United States |