C9orf72/ALFA-1 controls TFEB/HLH-30-dependent metabolism through dynamic regulation of Rag GTPases


Autoři: Yon Ju Ji aff001;  Janet Ugolino aff001;  Tao Zhang aff001;  Jiayin Lu aff001;  Dohoon Kim aff001;  Jiou Wang aff001
Působiště autorů: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America aff001;  Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, United States of America aff002
Vyšlo v časopise: C9orf72/ALFA-1 controls TFEB/HLH-30-dependent metabolism through dynamic regulation of Rag GTPases. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008738
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008738

Souhrn

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.

Klíčová slova:

Autophagic cell death – Caenorhabditis elegans – Co-immunoprecipitation – Guanosine triphosphatase – Lipids – Lysosomes – Phosphorylation – Diapause


Zdroje

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