An intrinsic mechanism of secreted protein aging and turnover

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.glycosylation | protein | homeostasis | glycosidase | lectin

Human Plasma N-glycosylation as Analyzed by Matrix-Assisted Laser Desorption/Ionization-Fourier Transform Ion Cyclotron Resonance-MS Associates with Markers of Inflammation and Metabolic Health

“…Additionally, increased levels of glycoproteins with exposed galactose residues can reflect a modulation of protein turnover, e.g. recycling by the liver-based asialoglycoprotein receptors (5,(91)(92)(93). Low sialylation would induce rapid turnover of lipid scavengers like alpha-1-acid glycoprotein, a situation which is beneficial when the blood needs to be cleared of high levels of lipophilic compounds.…”

“…Examples include quality control during protein folding, regulation of circulatory half-life, and modulation of receptor interactions by either providing the recognition motif or by affecting protein conformation (1)(2)(3)(4)(5)(6)(7). Consequentially, glycosylation has been associated with a multitude of diseases and states thereof, among which the progression and metastasis of cancer and the remission of rheumatoid arthritis (8 -11).…”

Glycomics: revealing the dynamic ecology and evolution of sugar molecules

“…Glycans also change with cell age. The Aswell receptor monitors deglycosylation as a sign that a cell or plasma glycoprotein needs recycling [7]. Glycans exist in organisms as clouds of variants whose properties integrate evolutionary and ecological information.…”

“…The asialoglycoprotein (Ashwell) receptor binds aging platelets, RBCs and glycoproteins so they can be removed from circulation [26] [7]. This same receptor mitigates bacterial infection [27].…”

Tay–Sachs disease mutations in HEXA target the α chain of hexosaminidase A to endoplasmic reticulum–associated degradation

“…In the Golgi apparatus, specific glycans are modified with mannose-6-phosphate (M6P), allowing for the trafficking of Hex enzymes to lysosomes (Sonderfeld-Fresko and Proia, 1989; Weitz and Proia, 1992). However, this recognition and transport is not entirely efficient, resulting in constitutive secretion both in vitro and in vivo (Hasilik and Neufeld, 1980; Yang et al. , 2015).…”