PICALM regulates cathepsin D processing and lysosomal function
Abstract
Degradation and clearance of cellular waste in the autophagic and endo-lysosomal systems is important for normal physiology and prevention of common late-onset diseases such as Alzheimer's disease (AD). Phosphatidylinostol-binding clathrin assembly protein (PICALM) is a robust AD risk factor gene and encodes an endosomal protein clathrin-binding cytosolic protein, reduction of which is known to exacerbate tauopathy. Although PICALM is known to regulate initiation of autophagy, its role in maturation of lysosomal enzymes required for proteolysis has not been studied. We sought to determine the importance of PICALM for cellular degradative function by disrupting exon 1 of PICALM using CRISPR/Cas9 in HeLa cells. PICALM disruption increased numbers of early endosomes. Proteomic analysis of endosome-enriched samples showed that disrupting exon 1 of PICALM increased the abundance of lysosomal enzymes in these organelles, and western blotting revealed disruption to processing and maturation of the lysosomal protease, cathepsin D, and a deficit in autophagy. This study shows PICALM is important for the correct maturation of lysosomal enzymes and efficient proteolytic function in the lysosome.
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- Authors
- Hattersley, K. J., Carosi, J. M., Hein, L. K., Bensalem, J., & Sargeant, T. J.
- Affiliations
- South Australian Health and Medical Research Institute (AU)
- Corresponding author
- Sargeant, Timothy J.
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 570
- Pages
- 103-109
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W3185851432
- Semantic Scholar
- 0d3415dcc41bc90af10e7f7f22255cad437506e2
- Cited by
- 10
- References
- 27
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 2
- FWCI
- 0.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Macquarie University
- Rebecca L. Cooper Medical Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- PICALM, cathepsin D, lysosomal function, early endosomes, autophagy, exon 1 deletion, lysosomal proteolysis
- MeSH terms
- Cathepsin D, Exons, HeLa Cells, Humans, Lysosomes, Protein Processing, Post-Translational, Endosomes, Substrate Specificity, Protein Isoforms, Monomeric Clathrin Assembly Proteins
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