Journal Article

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

Caballero, Benjamin, Cortopassi, Wilian A., Butler, Victoria J., Gao, Fuying, Coppola, Giovanni, Vohra, Mihir, Corrales, Christian I., Ashrafi, Kaveh, Jacobson, Matthew P., Kao, Aimee W., Cuervo, Ana Maria

2019

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aging / Aging - genetics / Amino acid composition / Animals / Animals, Genetically Modified / Autophagy / Backup software / Basic Helix-Loop-Helix Transcription Factors - metabolism / Bioinformatics / Biology and Life Sciences / Biosynthesis / Caenorhabditis elegans / Caenorhabditis elegans Proteins - metabolism / Chemistry / Dementia / Disease / Disease Models, Animal / DNA / DNA-Binding Proteins - genetics / Endopeptidases - metabolism / Enzymes / Funding / Geffen, David / Gene expression / Gene Expression Regulation / Genetic aspects / Granulin / Granulins - genetics / Granulins - metabolism / Homeostasis / Humans / Hydrophobicity / Lysosomes / Lysosomes - metabolism / Medicine / Medicine and Health Sciences / Memory / Molecular biology / Mutation / Nervous system diseases / Neurodegenerative diseases / Neurodegenerative Diseases - genetics / Neurodegenerative Diseases - pathology / Neurology / Neurophysiology / Neurosciences / Nuclear transport / Observations / Pathogenesis / Peptides / Phagocytosis / Physiological aspects / Physiological regulation / Physiology / Production increases / Proteases / Protein binding / Proteinase / Proteins / Research and Analysis Methods / Stress, Physiological - genetics / Toxicity / Transcription (Genetics)