An intrinsic mechanism of secreted protein aging and turnover

Significance In the blood, secreted proteins have different life spans that determine their abundance and function. Measurements of plasma protein composition and biological activities remain important for many clinical diagnoses. However the molecular mechanisms by which secreted proteins age and turnover have remained unidentified. The findings of this research have established an intrinsic and constitutive mechanism of secreted protein aging and turnover. This mechanism involves multiple factors including circulating glycosidases that progressively remodel the N-glycan linkages attached to most secreted proteins. N-glycan remodeling with time exposes glycan ligands of various endocytic lectin receptors that then eliminate these aged secreted proteins. This mechanism thereby determines the life spans and abundance of secreted proteins, and modulates the pathogenesis and outcomes of disease. 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.

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