RRC ID 65181
Author Ji YJ, Ugolino J, Zhang T, Lu J, Kim D, Wang J.
Title C9orf72/ALFA-1 controls TFEB/HLH-30-dependent metabolism through dynamic regulation of Rag GTPases.
Journal PLoS Genet
Abstract Nutrient utilization and energy metabolism are critical for the maintenance of cellular homeostasis. A mutation in the C9orf72 gene has been linked to the most common forms of neurodegenerative diseases that include amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we have identified an evolutionarily conserved function of C9orf72 in the regulation of the transcription factor EB (TFEB), a master regulator of autophagic and lysosomal genes that is negatively modulated by mTORC1. Loss of the C. elegans orthologue of C9orf72, ALFA-1, causes the nuclear translocation of HLH-30/TFEB, leading to activation of lipolysis and premature lethality during starvation-induced developmental arrest in C. elegans. A similar conserved pathway exists in human cells, in which C9orf72 regulates mTOR and TFEB signaling. C9orf72 interacts with and dynamically regulates the level of Rag GTPases, which are responsible for the recruitment of mTOR and TFEB on the lysosome upon amino acid signals. These results have revealed previously unknown functions of C9orf72 in nutrient sensing and metabolic pathways and suggest that dysregulation of C9orf72 functions could compromise cellular fitness under conditions of nutrient stress.
Volume 16(4)
Pages e1008738
Published 2020-4-1
DOI 10.1371/journal.pgen.1008738
PMID 32282804
PMC PMC7188304
MeSH Active Transport, Cell Nucleus Animals Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism* C9orf72 Protein / genetics C9orf72 Protein / metabolism* Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Nucleus / metabolism Lipolysis* Lysosomes / metabolism Mechanistic Target of Rapamycin Complex 1 / metabolism Monomeric GTP-Binding Proteins / genetics Monomeric GTP-Binding Proteins / metabolism
C.elegans tm1978