RRC ID 59457
Author Butler VJ, Gao F, Corrales CI, Cortopassi WA, Caballero B, Vohra M, Ashrafi K, Cuervo AM, Jacobson MP, Coppola G, Kao AW.
Title Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response.
Journal PLoS Genet
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.
Volume 15(8)
Pages e1008295
Published 2019-8-1
DOI 10.1371/journal.pgen.1008295
PMID 31398187
PMC PMC6703691
MeSH Aging / genetics Animals Animals, Genetically Modified Basic Helix-Loop-Helix Transcription Factors / metabolism* Caenorhabditis elegans Caenorhabditis elegans Proteins / metabolism* DNA-Binding Proteins / genetics* Disease Models, Animal Endopeptidases / metabolism Gene Expression Regulation Granulins / genetics Granulins / metabolism* Humans Lysosomes / metabolism* Neurodegenerative Diseases / genetics* Neurodegenerative Diseases / pathology Stress, Physiological / genetics
IF 5.224
Times Cited 1
C.elegans tm985 tm1978 tm4450