Characterization of human lysosomal neuraminidase defines the molecular basis of the metabolic storage disorder sialidosis.
Open accessAbstract
Neuraminidases (sialidases) have an essential role in the removal of terminal sialic acid residues from sialoglycoconjugates and are distributed widely in nature. The human lysosomal enzyme occurs in complex with beta-galactosidase and protective protein/cathepsin A (PPCA), and is deficient in two genetic disorders: sialidosis, caused by a structural defect in the neuraminidase gene, and galactosialidosis, in which the loss of neuraminidase activity is secondary to a deficiency of PPCA. We identified a full-length cDNA clone in the dbEST data base, of which the predicted amino acid sequence has extensive homology to other mammalian and bacterial neuraminidases, including the F(Y)RIP domain and "Asp-boxes." In situ hybridization localized the human neuraminidase gene to chromosome band 6p21, a region known to contain the HLA locus. Transient expression of the cDNA in deficient human fibroblasts showed that the enzyme is compartmentalized in lysosomes and restored neuraminidase activity in a PPCA-dependent manner. The authenticity of the cDNA was verified by the identification of three independent mutations in the open reading frame of the mRNA from clinically distinct sialidosis patients. Coexpression of the mutant cDNAs with PPCA failed to generate neuraminidase activity, confirming the inactivating effect of the mutations. These results establish the molecular basis of sialidosis in these patients, and clearly identify the cDNA-encoded protein as lysosomal neuraminidase.
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NEU1 is a ubiquitously expressed mammalian sialidase located in lysosomes and on the cell membrane.
“The ubiquitously expressed NEU1 is the most abundant homolog, shares the least sequence similarity with its family members, and is active on oligosaccharides, glycopeptides, and glycoproteins (1, 12–16). It is located in lysosomes and on the cell surface (12, 14, 15, 17, 18).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [12]
The Expression of human neuraminidase mRNA section reports a transcript in all human tissues tested, and Subcellular localization and enzymatic activation shows lysosome-like distribution. The paper does not establish that this enzyme is on the cell surface; it discusses a plasma-membrane neuraminidase as apparently distinct from the lysosomal enzyme. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNEU1 is unique among all known sialidases in that it requires an accessory protein for activity.
“NEU1 is unique among all known mammalian, microbial, or viral sialidases, as it requires an accessory protein for activity—the protective protein cathepsin A (CTSA; PPCA) (12, 19–23).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [12]
The ‘Subcellular localization and enzymatic activation’ section (page unavailable) says PPCA is essential for human lysosomal neuraminidase activity. The paper does not establish the further claim that this requirement is unique among all known mammalian, microbial, and viral sialidases. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNEU1 requires an accessory protein for activity-the protective protein cathepsin A (CTSA; PPCA).
“NEU1 is unique among all known mammalian, microbial, or viral sialidases, as it requires an accessory protein for activity—the protective protein cathepsin A (CTSA; PPCA) (12, 19–23).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [12]
CTSA is sufficient for NEU1 activity, whereas GLB1 is not necessary.
“However, CTSA is sufficient for NEU1 activity, whereas GLB1 is not necessary (12, 21–24, 27, 32).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [12]
GLB1 is not necessary for NEU1 activity and may compete with NEU1 for access to CTSA.
“Whereas a third enzyme—the glycosidase GLB1—has often been reported as a member of the high–molecular weight NEU1-CTSA complex (15, 27), GLB1 is not necessary for NEU1 activity (12, 21–24, 27, 32) and may compete with NEU1 for access to CTSA (12, 32).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [12]
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Structure of the immunoregulatory sialidase NEU1
Gorelik, A., Illes, K., Mazhab-Jafari, M. T., & Nagar, B. (2023) · Science Advances · doi:10.1126/sciadv.adf8169 · Cited by 36 · see citing works
- Authors
- Bonten, E., van der Spoel, A., Fornerod, M., Grosveld, G., & d'Azzo, A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1996-12-15
- Volume
- 10
- Issue
- 24
- Pages
- 3156-3169
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2148235564
- Cited by
- 313
- References
- 2
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 13 · 2023: 6 · 2022: 15 · 2021: 17 · 2020: 17 · 2019: 15 · 2018: 18 · 2017: 11 · 2016: 8 · 2015: 9 · 2014: 10 · 2013: 10 · 2012: 16
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- St. Jude Children's Research Hospital
- American Lebanese Syrian Associated Charities
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Keywords
- sialidosis, galactosialidosis, PpcA, beta-galactosidase, sialic acid removal, cDNA cloning, chromosome 6p21, HLA locus, loss-of-function mutations, lysosomal storage disease
- MeSH terms
- Amino Acid Sequence, Base Sequence, Chromosome Mapping, Chromosomes, Human, Pair 6, Genetic Complementation Test, Humans, Lysosomes, Molecular Sequence Data, Neuraminidase, RNA, Messenger, Gene Expression, Gene Expression Regulation, Enzymologic, Sequence Alignment, Lysosomal Storage Diseases, Sequence Homology, Amino Acid, In Situ Hybridization, Fluorescence, DNA, Complementary
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