Cathepsin A regulates chaperone‐mediated autophagy through cleavage of the lysosomal receptor
Open accessAbstract
Protective protein/cathepsin A (PPCA) has a serine carboxypeptidase activity of unknown physiological function. We now demonstrate that this protease activity triggers the degradation of the lysosome-associated membrane protein type 2a (lamp2a), a receptor for chaperone-mediated autophagy (CMA). Degradation of lamp2a is important because its level in the lysosomal membrane is a rate-limiting step of CMA. Cells defective in PPCA show reduced rates of lamp2a degradation, higher levels of lamp2a and higher rates of CMA. Restoration of PPCA protease activity increases rates of lamp2a degradation, reduces levels of lysosomal lamp2a and reduces rates of CMA. PPCA associates with lamp2a on the lysosomal membrane and cleaves lamp2a near the boundary between the luminal and transmembrane domains. In addition to the well-studied role of PPCA in targeting and protecting two lysosomal glycosidases, we have defined a role for the proteolytic activity of this multifunctional protein.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PPCA co-purified with LAMP2a in lysosomal preparations from rat liver, indicating that cathepsin A alone or in complex controls LAMP2a turnover, and PPCA-deficient fibroblasts show reduced LAMP2a degradation and increased chaperone-mediated autophagy.
“It was shown that in lysosomal preparations isolated from rat liver PPCA co-purified with LAMP2a, indicating that cathepsin A alone or in complex controls the turnover of LAMP2a 51.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [51]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
No references could be resolved yet.
Research works printed but not linked: 3
- 'Azzo,A., Hoogeveen,A., Reuser,A.J., Robinson,D. and Galjaard,H. (1982) Molecular defect in combined b-galactosidase and neuraminidase de®ciency in man. Proc. Natl Acad. Sci. USA, 79, 4535±4539.
- 'Azzo,A., Andria,G., Strisciuglio,P. and Galijaard,H. (1995) Galactosialidosis. In Scriver,C., Beaudet,A., Sly,W. and Valle,D. (eds), Metabolic and Molecular Bases of Inherited Disease. McGraw- Hill, New York, NY, pp. 2835±2837.
- Towbin,H., Staehelin,T. and Gordon,J. (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedures and some applications. Proc. Natl Acad. Sci. USA, 76, 4350±4353.
Cited by
Sorted by citations
Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson’s disease
Murphy, K. E., Gysbers, A. M., Abbott, S. K., Tayebi, N., Kim, W. S., Sidransky, E., Cooper, A., Garner, B., & Halliday, G. M. (2014) · Brain · doi:10.1093/brain/awt367 · Cited by 475 · see citing works
Gómez-Virgilio, L., Silva-Lucero, M.-D.-C., Flores-Morelos, D.-S., Gallardo-Nieto, J., Lopez-Toledo, G., Abarca-Fernandez, A.-M., Zacapala-Gómez, A.-E., Luna-Muñoz, J., Montiel-Sosa, F., Soto-Rojas, L. O., et al. (2022) · Cells · doi:10.3390/cells11152262 · Cited by 431 · see citing works
Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein
Bauer, P. O., Goswami, A., Wong, H. K., Okuno, M., Kurosawa, M., Yamada, M., Miyazaki, H., Matsumoto, G., Kino, Y., Nagai, Y., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1608 · Cited by 280 · see citing works
Yu, W. H., Kumar, A., Peterhoff, C., Shapiro Kulnane, L., Uchiyama, Y., Lamb, B. T., Cuervo, A. M., & Nixon, R. A. (2004) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.05.010 · Cited by 279 · see citing works
Self-citationChaperone-mediated autophagy: selectivity pays off
Cuervo, A. M. (2010) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2009.10.003 · Cited by 260 · see citing works
“Degradation is initiated through dual cleavage by a pair of lysosomal proteases, cathepsin A and a yet unidentified metalloprotease, followed by the release of the truncated form of LAMP-2A in the lumen and its complete degradation by resident hydrolases [50].”
BackgroundSelf-citationAltered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age
Kiffin, R., Kaushik, S., Zeng, M., Bandyopadhyay, U., Zhang, C., Massey, A. C., Martinez-Vicente, M., & Cuervo, A. M. (2007) · Journal of Cell Science · doi:10.1242/jcs.001073 · Cited by 213 · see citing works
Self-citationGalactosialidosis: 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
Self-citationGalactosialidosis: historic aspects and overview of investigated and emerging treatment options
Annunziata, I., & d’Azzo, A. (2017) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2016.1266933 · Cited by 50 · see citing works
Self-citationTargeting Lysosomal Dysfunction to Alleviate Plaque Deposition in an Alzheimer Disease Model
Fremuth, L. E., van de Vlekkert, D., Hu, H., Weesner, J. A., Annunziata, I., Yogalingam, G., & d’Azzo, A. (2025) · doi:10.1101/2025.04.28.651121 · Cited by 1 · see citing works
Self-citation
- Authors
- Cuervo, A. M., Mann, L., Bonten, E. J., d'Azzo, A., & Dice, J. F.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Tufts University (US)
- Venue
- The EMBO Journal
- Published
- 2003-01-02
- Volume
- 22
- Issue
- 1
- Pages
- 47-59
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC140041
- OpenAlex
- W2013389256
- Cited by
- 182
- References
- 0
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 12 · 2020: 4 · 2019: 8 · 2018: 12 · 2017: 11 · 2016: 4 · 2015: 6 · 2014: 8 · 2013: 13 · 2012: 9
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (DK-52025)
- National Institute on Aging (AG00829, AG-06116, R01AG006116, R37AG006116)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-52025, Z01DK052025, R01DK052025)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- cathepsin A, chaperone-mediated autophagy, LAMP2A, lysosomal membrane, proteolytic cleavage, lysosomal glycosidases, lysosome-associated membrane protein
- MeSH terms
- Amino Acid Sequence, Animals, Autophagy, Carboxypeptidases, Cytosol, Intracellular Membranes, Kinetics, Lysosomes, Male, Mice, Inbred C57BL, Molecular Sequence Data, Serine Endopeptidases, Antigens, CD, Bone Marrow Transplantation, Rats, Wistar, Molecular Chaperones, Cathepsin A, Mice, Rats, Lysosomal Membrane Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
