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.
N1 - Funding Information:
This work was supported by National Institutes of Health R21 NS082709, R01 NS095257, R01 AG059052, the Paul G. Allen Family Foundation, the Glenn Award for Research in Biological Mechanisms of Aging, the Alzheimer’s Disease Research Center, the Consortium for Frontotemporal Dementia Research, the John Douglas French Alzheimer’s Foundation and the Brain Research Foundation (A.W.K.). We also thank The James and Barbara Knuppe Family Foundation for research support. Additional support was provided by NIH (RC1 AG035610), the NINDS Informatics Center for Neurogenetics and Neurogenomics (P30 NS062691) and the John Douglas French Alzheimer’s Foundation (G. C.), the Rainwater Foundation (A.M.C.) and NIH (R01 AG046400) (K.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2019 Butler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019
Y1 - 2019
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.
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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 -