An Intrinsic Mechanism of Secreted Protein Aging and Turnover

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Oct 23

PMID 26489654

Citations 56

Authors

Won Ho Yang

Peter V Aziz

Douglas M Heithoff

Michael J Mahan

Jeffrey W Smith

Jamey D Marth

Affiliations

Soon will be listed here.

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.

Citing Articles

Engineering of anticancer human immunoglobulin A equipped with albumin for enhanced plasma half-life.

Mester S, Chan C, Lustig M, Foss S, Jansen J, Leangen Herigstad M PNAS Nexus. 2025; 4(2):pgaf042.

PMID: 40041621 PMC: 11878800. DOI: 10.1093/pnasnexus/pgaf042.

IgA displays site- and subclass-specific glycoform differences despite equal glycoenzyme expression.

Falck D, Sokolova M, Koeleman C, Irumva V, Kirchner P, Schulz S Cell Commun Signal. 2025; 23(1):92.

PMID: 39962487 PMC: 11834270. DOI: 10.1186/s12964-025-02088-0.

MYO18B promotes lysosomal exocytosis by facilitating focal adhesion maturation.

Ren W, Kawahara R, Suzuki K, Dipta P, Yang G, Thaysen-Andersen M J Cell Biol. 2025; 224(3).

PMID: 39751400 PMC: 11697975. DOI: 10.1083/jcb.202407068.

ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE mice.

Svecla M, Moregola A, Da Dalt L, Nour J, Baragetti A, Uboldi P Cardiovasc Diabetol. 2024; 23(1):428.

PMID: 39616371 PMC: 11608471. DOI: 10.1186/s12933-024-02507-5.

Sialic acids on T cells are crucial for their maintenance and survival.

Schmidt M, Linder A, Korn M, Schellenberg N, Meyer S, Nimmerjahn F Front Immunol. 2024; 15:1359494.

PMID: 38947328 PMC: 11211268. DOI: 10.3389/fimmu.2024.1359494.

References

Coxon A, Rieu P, Barkalow F, Askari S, Sharpe A, von Andrian U . A novel role for the beta 2 integrin CD11b/CD18 in neutrophil apoptosis: a homeostatic mechanism in inflammation. Immunity. 1996; 5(6):653-66. DOI: 10.1016/s1074-7613(00)80278-2. View

Hata K, Koseki K, Yamaguchi K, Moriya S, Suzuki Y, Yingsakmongkon S . Limited inhibitory effects of oseltamivir and zanamivir on human sialidases. Antimicrob Agents Chemother. 2008; 52(10):3484-91. PMC: 2565904. DOI: 10.1128/AAC.00344-08. View

Grewal P, Aziz P, Uchiyama S, Rubio G, Lardone R, Le D . Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor. Proc Natl Acad Sci U S A. 2013; 110(50):20218-23. PMC: 3864324. DOI: 10.1073/pnas.1313905110. View

Grozovsky R, Jurak Begonja A, Liu K, Visner G, Hartwig J, Falet H . The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med. 2014; 21(1):47-54. PMC: 4303234. DOI: 10.1038/nm.3770. View

Rice K, Lee Y . Modification of triantennary glycopeptide into probes for the asialoglycoprotein receptor of hepatocytes. J Biol Chem. 1990; 265(30):18423-8. View

Soukharev S, Miller J, Sauer B . Segmental genomic replacement in embryonic stem cells by double lox targeting. Nucleic Acids Res. 1999; 27(18):e21. PMC: 148613. DOI: 10.1093/nar/27.18.e21. View

Szajda S, Waszkiewicz N, Stypulkowska A, Dadan J, Zwierz K . Lysosomal exoglycosidases in serum and urine of patients with pancreatic adenocarcinoma. Folia Histochem Cytobiol. 2010; 48(3):351-7. DOI: 10.2478/v10042-010-0060-9. View

Rigat B, Tropak M, Buttner J, Crushell E, Benedict D, Callahan J . Evaluation of N-nonyl-deoxygalactonojirimycin as a pharmacological chaperone for human GM1 gangliosidosis leads to identification of a feline model suitable for testing enzyme enhancement therapy. Mol Genet Metab. 2012; 107(1-2):203-12. PMC: 4010500. DOI: 10.1016/j.ymgme.2012.06.007. View

Stamatos N, Carubelli I, van de Vlekkert D, Bonten E, Papini N, Feng C . LPS-induced cytokine production in human dendritic cells is regulated by sialidase activity. J Leukoc Biol. 2010; 88(6):1227-39. PMC: 2996894. DOI: 10.1189/jlb.1209776. View

10.

Bonten E, Van der Spoel A, Fornerod M, Grosveld G, dAzzo A . Characterization of human lysosomal neuraminidase defines the molecular basis of the metabolic storage disorder sialidosis. Genes Dev. 1996; 10(24):3156-69. DOI: 10.1101/gad.10.24.3156. View

11.

Corfield T . Bacterial sialidases--roles in pathogenicity and nutrition. Glycobiology. 1992; 2(6):509-21. DOI: 10.1093/glycob/2.6.509. View

12.

States D, Omenn G, Blackwell T, Fermin D, Eng J, Speicher D . Challenges in deriving high-confidence protein identifications from data gathered by a HUPO plasma proteome collaborative study. Nat Biotechnol. 2006; 24(3):333-8. DOI: 10.1038/nbt1183. View

13.

Tozawa R, Ishibashi S, Osuga J, Yamamoto K, Yagyu H, Ohashi K . Asialoglycoprotein receptor deficiency in mice lacking the major receptor subunit. Its obligate requirement for the stable expression of oligomeric receptor. J Biol Chem. 2001; 276(16):12624-8. DOI: 10.1074/jbc.M011063200. View

14.

Kawasaki T, ASHWELL G . Isolation and characterization of an avian hepatic binding protein specific for N-acetylglucosamine-terminated glycoproteins. J Biol Chem. 1977; 252(18):6536-43. View

15.

Taylor M, Drickamer K . Convergent and divergent mechanisms of sugar recognition across kingdoms. Curr Opin Struct Biol. 2014; 28:14-22. PMC: 4444583. DOI: 10.1016/j.sbi.2014.07.003. View

16.

Cross A, Hyun S, Miranda-Ribera A, Feng C, Liu A, Nguyen C . NEU1 and NEU3 sialidase activity expressed in human lung microvascular endothelia: NEU1 restrains endothelial cell migration, whereas NEU3 does not. J Biol Chem. 2012; 287(19):15966-80. PMC: 3346112. DOI: 10.1074/jbc.M112.346817. View

17.

Taylor M, Conary J, Lennartz M, Stahl P, Drickamer K . Primary structure of the mannose receptor contains multiple motifs resembling carbohydrate-recognition domains. J Biol Chem. 1990; 265(21):12156-62. View

18.

Grewal P, Uchiyama S, Ditto D, Varki N, Le D, Nizet V . The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Nat Med. 2008; 14(6):648-55. PMC: 2853759. DOI: 10.1038/nm1760. View

19.

Schachter H . Complex N-glycans: the story of the "yellow brick road". Glycoconj J. 2013; 31(1):1-5. DOI: 10.1007/s10719-013-9507-5. View

20.

KORNFELD R, Kornfeld S . Assembly of asparagine-linked oligosaccharides. Annu Rev Biochem. 1985; 54:631-64. DOI: 10.1146/annurev.bi.54.070185.003215. View