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.
| Original language | English (US) |
|---|---|
| Article number | e1008295 |
| Journal | PLoS genetics |
| Volume | 15 |
| Issue number | 8 |
| DOIs | |
| State | Published - Jan 1 2019 |
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ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Molecular Biology
- Genetics
- Genetics(clinical)
- Cancer Research
Cite this
Age- And stress-associated C. Elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response. / Butler, Victoria J.; Gao, Fuying; Corrales, Christian I.; Cortopassi, Wilian A.; Caballero, Benjamin; Vohra, Mihir; Ashrafi, Kaveh; Cuervo, Ana Maria; Jacobson, Matthew P.; Coppola, Giovanni; Kao, Aimee W.
In: PLoS genetics, Vol. 15, No. 8, e1008295, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Age- And stress-associated C. Elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response
AU - Butler, Victoria J.
AU - Gao, Fuying
AU - Corrales, Christian I.
AU - Cortopassi, Wilian A.
AU - Caballero, Benjamin
AU - Vohra, Mihir
AU - Ashrafi, Kaveh
AU - Cuervo, Ana Maria
AU - Jacobson, Matthew P.
AU - Coppola, Giovanni
AU - Kao, Aimee W.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85071707022&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071707022&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1008295
DO - 10.1371/journal.pgen.1008295
M3 - Article
C2 - 31398187
AN - SCOPUS:85071707022
VL - 15
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 8
M1 - e1008295
ER -