An intrinsic mechanism of secreted protein aging and turnover.

TitleAn intrinsic mechanism of secreted protein aging and turnover.
Publication TypeJournal Article
Year of Publication2015
AuthorsYang WHo, Aziz PV, Heithoff DM, Mahan MJ, Smith JW, Marth JD
JournalProc Natl Acad Sci U S A
Volume112
Issue44
Pagination13657-62
Date Published2015 Nov 3
ISSN1091-6490
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.

DOI10.1073/pnas.1515464112
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID26489654
PubMed Central IDPMC4640737
Grant ListDK14842 / 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