Association of N-Acetylgalactosamine-6-sulfate Sulfatase with the Multienzyme Lysosomal Complex of β-Galactosidase, Cathepsin A, and Neuraminidase
Open accessAbstract
N-Acetylgalactosamine-6-sulfate sulfatase (GALNS) catalyzes the first step of intralysosomal keratan sulfate (KS) catabolism. In Morquio type A syndrome GALNS deficiency causes the accumulation of KS in tissues and results in generalized skeletal dysplasia in affected patients. We show that in normal cells GALNS is in a 1.27-MDa complex with three other lysosomal hydrolases: beta-galactosidase, alpha-neuraminidase, and cathepsin A (protective protein). GALNS copurifies with the complex by different chromatography techniques: affinity chromatography on both cathepsin A-binding and beta-galactosidase-binding columns, gel filtration, and chromatofocusing. Anti-human cathepsin A rabbit antiserum coprecipitates GALNS together with cathepsin A, beta-galactosidase, and alpha-neuraminidase in both a purified preparation of the 1. 27-MDa complex and crude glycoprotein fraction from human placenta extract. Gel filtration analysis of fibroblast extracts of patients deficient in either beta-galactosidase (beta-galactosidosis) or cathepsin A (galactosialidosis), which accumulate KS, demonstrates that the 1.27-MDa complex is disrupted and that GALNS is present only in free homodimeric form. The GALNS activity and cross-reacting material are reduced in the fibroblasts of patients affected with galactosialidosis, indicating that the complex with cathepsin A may protect GALNS in the lysosome. We suggest that the 1.27-MDa complex of lysosomal hydrolases is essential for KS catabolism and that the disruption of this complex may be responsible for the KS accumulation in beta-galactosidosis and galactosialidosis patients.
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NEU1 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 [21]
The GALNS introduction (page not provided) says that the lysosomal complex containing cathepsin A is necessary for neuraminidase activation. The Results and Discussion likewise says association with cathepsin A is sufficient for its activity. Neither passage establishes that NEU1 is unique among mammalian, microbial, and viral sialidases in requiring an accessory protein. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGLB1 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 [21]
In Results and Discussion (page not provided), the paper reports normal NEUR activity in β-galactosidosis fibroblasts lacking the usual complex and says association with CathA alone is sufficient for NEUR activity. This supports GLB1 not being necessary, but the paper does not say that GLB1 may compete with NEU1 for access to CTSA. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCTSA 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 [21]
NEU1 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 [21]
NEU1 and CTSA can associate into large complexes in the absence of GLB1.
“Accordingly, NEU1 and CTSA can also associate into large complexes in the absence of GLB1 (21, 22).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [21]
The reported 104-kDa heterodimeric complex does not match the large aggregates resulting in coprecipitation of both proteins or the megadalton-size complexes in vivo.
“This finding does not match the large aggregates resulting in coprecipitation of both proteins described above or the megadalton-size complexes in vivo (21, 22).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [21]
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Research works printed but not linked: 5
- Neufeld, E. F., and Muenzer, J. (1995) in The Metabolic and Molecular Bases of Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds) Vol. 2, McGraw-Hill, New York
- d'Azzo, A., Hoogeveen, A., Reuser, A. J., Robinson, D., and Galjaard, H. (1982) Proc. Natl. Acad. Sci. U. S. A. 79, 4535-4539
- van der Horst, G. T. J. (1993) Ph.D. thesis, Erasmus University Press, Amsterdam
- Suzuki, Y., Sakuraba, H., and Oshima, A. (1995)in The Metabolic and Molec- ular Bases of Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds) vol. 2, McGraw-Hill, New York
- Thomas, G. H., and Beaudet, A. L. (1995) in The Metabolic and Molecular Bases of Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds) vol. 2, McGraw-Hill, New York FIG.
Cited by
Sorted by citations
Galactosialidosis: review and analysis of CTSA gene mutations
Caciotti, A., Catarzi, S., Tonin, R., Lugli, L., Perez, C. R., Michelakakis, H., Mavridou, I., Donati, M. A., Guerrini, R., d’Azzo, A., et al. (2013) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-8-114 · Cited by 73 · see citing works
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
- Pshezhetsky, A. V., & Potier, M.
- Affiliations
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Corresponding author
- Pshezhetsky, Alexey V.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1996-11
- Volume
- 271
- Issue
- 45
- Pages
- 28359-28365
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2168057450
- Cited by
- 90
- References
- 0
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 2 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 4 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 4 · 2013: 8 · 2012: 6
- FWCI
- 1.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Medical Research Council Canada
- Medical Research Council
- 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 › Cell Biology › Proteoglycans and glycosaminoglycans research
- Keywords
- N-acetylgalactosamine-6-sulfate sulfatase, beta-galactosidase, cathepsin A, galactosialidosis, lysosomal storage disease, glycoprotein complex
- MeSH terms
- Animals, beta-Galactosidase, Carboxypeptidases, Chondroitinsulfatases, Chromatography, Gel, Chromatography, High Pressure Liquid, Humans, Isoelectric Focusing, Keratan Sulfate, Lysosomes, Multienzyme Complexes, Neuraminidase, Placenta, Rabbits, Cathepsin A
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