RRC ID |
59457
|
著者 |
Butler VJ, Gao F, Corrales CI, Cortopassi WA, Caballero B, Vohra M, Ashrafi K, Cuervo AM, Jacobson MP, Coppola G, Kao AW.
|
タイトル |
Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response.
|
ジャーナル |
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.
|
巻・号 |
15(8)
|
ページ |
e1008295
|
公開日 |
2019-8-1
|
DOI |
10.1371/journal.pgen.1008295
|
PII |
PGENETICS-D-19-00480
|
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
|
引用数 |
1
|
リソース情報 |
線虫 |
tm985
tm1978
tm4450 |