Protective protein/cathepsin A rescues N-glycosylation defects in neuraminidase-1

D Wang, S Zaitsev, Garry Lindsay Taylor, A d'Azzo, E Bonten

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

Background: Neuraminidase-1 (NEU1) catabolizes the hydrolysis of sialic acids from sialo-glycoconjugates. NEU1 depends on its interaction with the protective protein/cathepsin A (PPCA) for lysosomal compartmentalization and catalytic activation. Murine NEU1 contains 4 N-glycosylation sites. 3 of which are conserved in the human enzyme. The expression of NEU1 gives rise to differentially glycosylated proteins.

Methods: We generated single-point mutations in mouse NEU1 at each of the 4 N-glycosylation sites. Mutant enzymes were expressed in NEU1-deficient cells in the presence and absence of PPCA.

Results: All 4 N-glycosylation variants were targeted to the lysosomal/endosomal compartment. All N-glycans, with the exception of the most C-terminal glycan, were important for maintaining stability or catalytic activity. The loss of catalytic activity caused by the deletion of the second N-glycan was rescued by increasing PPCA expression. Similar results were obtained with a human NEU1 N-glycosylation mutant identified in a sialidosis patient. The N-terminal N-glycan of NEU1 is indispensable for its function, whereas the C-terminal N-glycan appears to be non-essential. The omission of the second N-glycan can be compensated for by upregulating the expression of PPCA.

General significance: These findings could be relevant for the design of target therapies for patients carrying specific NEU1 mutations. (C) 2009 Elsevier B.V. Ail rights reserved.

Original languageEnglish
Pages (from-to)275-282
Number of pages8
JournalBiochimica et Biophysica Acta
Volume1790
DOIs
Publication statusPublished - Apr 2009

Keywords

  • Glycosylation
  • Sialidosis
  • Chaperone therapy
  • Neuraminidase
  • Sialidase
  • NEU1
  • Protective protein/cathepsin A
  • HUMAN LYSOSOMAL NEURAMINIDASE
  • PROTEIN
  • SIALIDOSIS
  • GALACTOSIALIDOSIS
  • CELLS
  • DEGLYCOSYLATION
  • SIALIDASE
  • GLYCANS
  • DOMAINS
  • ROLES

Fingerprint

Dive into the research topics of 'Protective protein/cathepsin A rescues N-glycosylation defects in neuraminidase-1'. Together they form a unique fingerprint.

Cite this