Enzymatic Activity of Lysosomal Carboxypeptidase (Cathepsin) A Is Required for Proper Elastic Fiber Formation and Inactivation of Endothelin-1
Abstract
Background— Lysosomal carboxypeptidase, cathepsin A (protective protein, CathA), is a component of the lysosomal multienzyme complex along with β-galactosidase (GAL) and sialidase Neu1, where it activates Neu1 and protects GAL and Neu1 against the rapid proteolytic degradation. On the cell surface, CathA, Neu1, and the enzymatically inactive splice variant of GAL form the elastin-binding protein complex. In humans, genetic defects of CathA cause galactosialidosis, a metabolic disease characterized by combined deficiency of CathA, GAL, and Neu1 and a lysosomal storage of sialylated glycoconjugates. However, several phenotypic features of galactosialidosis patients, including hypertension and cardiomyopathies, cannot be explained by the lysosomal storage. These observations suggest that CathA may be involved in hemodynamic functions that go beyond its protective activity in the lysosome. Methods and Results— We generated a gene-targeted mouse in which the active CathA was replaced with a mutant enzyme carrying a Ser190Ala substitution in the active site. These animals expressed physiological amounts of catalytically inactive CathA protein, capable of forming lysosomal multienzyme complex, and did not develop secondary deficiency of Neu1 and GAL. Conversely, the mice showed a reduced degradation rate of the vasoconstrictor peptide, endothelin-1, and significantly increased arterial blood pressure. CathA-deficient mice also displayed scarcity of elastic fibers in lungs, aortic adventitia, and skin. Conclusions— Our results provide the first evidence that CathA acts in vivo as an endothelin-1–inactivating enzyme and strongly confirm a crucial role of this enzyme in effective elastic fiber formation.
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CTSA-induced LDLR degradation depends on the protease activity of CTSA, as the catalytically inactive S190A mutant failed to induce LDLR degradation.
“This degradation depended on the protease activity of CTSA, as the expression of a catalytically inactive S190A mutant 33 failed to induce LDLR degradation (Fig. 4g).”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [33]
CathAS190A-Neo mice display drastically reduced Neu1 activity in most tissues due to destabilization of Ppca mRNA by the Neo cassette, but are vital, fertile, develop normally, and have a normal lifespan, suggesting that 10% NEU1 activity is sufficient to promote normal development and growth.
“Although the mutation targeted the Ppca locus, the CathAS190A-Neo mice displayed a drastically reduced activity of Neu1 in most tissues, due to destabilization of Ppca mRNA by the Neo cassette.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [47]
Cultured embryonic brain cells isolated from CathAS190A mice secrete higher levels of endothelin-1 and have reduced degradation rate of endothelin-1 in blood and tissues.
“In fact, cultured embryonic brain cells isolated from CathAS190A mice secrete higher levels of endothelin-1 and have reduced degradation rate of endothelin-1 in blood and tissues 47.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [47]
CathAS190A mice have an isolated deficiency of cathepsin A with intact protective properties toward NEU1 and normal Neu1 activity, show abnormalities in elastin-rich tissues such as skin, arteries, and lung with impaired deposition of insoluble elastin, and have significantly higher diastolic and systolic blood pressure than wild-type siblings.
“Upon removal of the Neo cassette from intron 7, the same authors successfully generated mice (CathAS190A) with an isolated deficiency of cathepsin A, but with intact protective properties toward NEU1; CathAS190A mice have normal Neu1 activity.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [47]
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Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover
Feng, X., Zhang, S., Wang, Y., Kurlagunda, T., Sit, A., Jaishankar, P., Yang, P., Sakane, S., Park, S. Y., Wisessaowapak, C., et al. (2026) · Nature · doi:10.1038/s41586-026-10697-z · Cited by 2 · see citing works
- Authors
- Seyrantepe, V., Hinek, A., Peng, J., Fedjaev, M., Ernest, S., Kadota, Y., Canuel, M., Itoh, K., Morales, C. R., Lavoie, J., Tremblay, J., & Pshezhetsky, A. V.
- Affiliations
- University of Toronto (CA)
- ORCID
- Venue
- Circulation
- Published
- 2008-04-15
- Volume
- 117
- Issue
- 15
- Pages
- 1973-1981
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2166139320
- Cited by
- 112
- References
- 0
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 2 · 2016: 8 · 2015: 7 · 2014: 8 · 2013: 9 · 2012: 10
- FWCI
- 6.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- cathepsin A, elastic fiber formation, galactosialidosis, beta-galactosidase, arterial blood pressure, hypertension, active site mutations, aortic adventitia, lung
- MeSH terms
- Animals, beta-Galactosidase, Blood Pressure, Cells, Cultured, Elastic Tissue, Elastin, Enzyme Activation, Fibroblasts, Genes, Synthetic, Hypertension, Lysosomes, Mice, Inbred C57BL, Multienzyme Complexes, Neuraminidase, Neurons, Organ Specificity, RNA, Messenger, Sodium Chloride, Dietary, Mice, Knockout, Endothelin-1, Cathepsin A, Mice
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