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Cited by 39Genetics, Aging, and Longevity in Model OrganismsAmyotrophic Lateral Sclerosis ResearchAutophagy in Disease and Therapy

Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response

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Butler, Victoria J., Gao, Fuying, Corrales, Christian I., Cortopassi, Wilian A., Caballero, Benjamin, Vohra, Mihir, Ashrafi, Kaveh, Cuervo, Ana Maria +3 more·2019·PLOS Genetics
DOI 10.1371/journal.pgen.1008295PMC PMC6703691
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Abstract

The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases are key contributors to the maintenance of protein homeostasis with age. We previously reported that expression of granulin peptides, the cleavage products of the neurodegenerative disease protein progranulin, enhance the accumulation and toxicity of TAR DNA binding protein 43 (TDP-43) in Caenorhabditis elegans (C. elegans). In this study we show that C. elegans granulins are produced in an age- and stress-dependent manner. Granulins localize to the endolysosomal compartment where they impair lysosomal protease expression and activity. Consequently, protein homeostasis is disrupted, promoting the nuclear translocation of the lysosomal transcription factor HLH-30/TFEB, and prompting cells to activate a compensatory transcriptional program. The three C. elegans granulin peptides exhibited distinct but overlapping functional effects in our assays, which may be due to amino acid composition that results in distinct electrostatic and hydrophobicity profiles. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease.

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  • Lysosomes are critical for apoptosis in two ways: lysosomal membrane permeabilization releases hydrolases into cytosol; dying cell must be engulfed by neighboring astrocytes and microglia into phagosomes, fuse with lysosomes, and be digested by lysosomal enzymes.

    “Lysosomes are critical for apoptosis in two ways. In the cell undergoing apoptosis, the lysosomal membrane is permeabilized in a controlled fashion, allowing the release of lysosomal hydrolases into the cytosol.23 To complete the process, the dying cell must be engulfed by neighboring astrocytes and microglia into phagosomes, fuse24,25with their lysosomes, and then be digested and cleared by lysos”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [25]

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Authors
Butler, V. J., Gao, F., Corrales, C. I., Cortopassi, W. A., Caballero, B., Vohra, M., Ashrafi, K., Cuervo, A. M., Jacobson, M. P., Coppola, G., & Kao, A. W.
Affiliations
  • University of California, San Francisco (US)
  • University of California, Los Angeles (US)
  • Albert Einstein College of Medicine (US)
Corresponding author
Kao, Aimee W.
ORCID
Venue
PLOS Genetics
Publisher
Public Library of Science (PLoS)
Published
2019-08-09
Volume
15
Issue
8
Pages
e1008295
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1008295
PMC
PMC6703691
OpenAlex
W2968404232
Cited by
39
References
7
Citations by year
2026: 3 · 2025: 7 · 2024: 5 · 2023: 10 · 2022: 3 · 2021: 8 · 2020: 3
FWCI
1.27
Type
journal article
Language
en
Update notices
new_version (2019-08-21)
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health (R21NS082709, R01NS095257, R01AG059052, RC1AG035610, R01AG046400)
  • National Institute of Neurological Disorders and Stroke (P30NS062691)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
granulin, progranulin, lysosomal proteases, lysosomal function, proteostasis, aging, stress response, TDP-43, autophagy, endolysosomal compartment, neurodegeneration, Caenorhabditis elegans, transcriptional response
MeSH terms
Granulins, Aging, Animals, Disease Models, Animal, DNA-Binding Proteins, Gene Expression Regulation, Humans, Lysosomes, Endopeptidases, Stress, Physiological, Caenorhabditis elegans, Neurodegenerative Diseases, Caenorhabditis elegans Proteins, Animals, Genetically Modified, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors

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