An intrinsic mechanism of secreted protein aging and turnover

Won Ho Yang, Peter V. Aziz, Douglas M. Heithoff, Michael J. Mahan, Jeffrey W. Smith, Jamey D. Marth

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)13657-13662
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number44
DOIs
Publication statusPublished - 2015 Nov 3

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Polysaccharides
Proteins
Glycoside Hydrolases
Neuraminidase
Lectins
Hexosaminidase B
Protein Deficiency
Intrinsic Factor
Proteome
beta-Galactosidase
Integrins
Macrophages
Ligands
Health

All Science Journal Classification (ASJC) codes

  • General

Cite this

Yang, Won Ho ; Aziz, Peter V. ; Heithoff, Douglas M. ; Mahan, Michael J. ; Smith, Jeffrey W. ; Marth, Jamey D. / An intrinsic mechanism of secreted protein aging and turnover. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 44. pp. 13657-13662.
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An intrinsic mechanism of secreted protein aging and turnover. / Yang, Won Ho; Aziz, Peter V.; Heithoff, Douglas M.; Mahan, Michael J.; Smith, Jeffrey W.; Marth, Jamey D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 44, 03.11.2015, p. 13657-13662.

Research output: Contribution to journalArticle

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