RRC ID 59559
Author Murphy JT, Liu H, Ma X, Shaver A, Egan BM, Oh C, Boyko A, Mazer T, Ang S, Khopkar R, Javaheri A, Kumar S, Jiang X, Ory D, Mani K, Matkovich SJ, Kornfeld K, Diwan A.
Title Simple nutrients bypass the requirement for HLH-30 in coupling lysosomal nutrient sensing to survival.
Journal PLoS Biol
Abstract Lysosomes are ubiquitous acidified organelles that degrade intracellular and extracellular material trafficked via multiple pathways. Lysosomes also sense cellular nutrient levels to regulate target of rapamycin (TOR) kinase, a signaling enzyme that drives growth and suppresses activity of the MiT/TFE family of transcription factors that control biogenesis of lysosomes. In this study, we subjected worms lacking basic helix-loop-helix transcription factor 30 (hlh-30), the Caenorhabditis elegans MiT/TFE ortholog, to starvation followed by refeeding to understand how this pathway regulates survival with variable nutrient supply. Loss of HLH-30 markedly impaired survival in starved larval worms and recovery upon refeeding bacteria. Remarkably, provision of simple nutrients in a completely defined medium (C. elegans maintenance medium [CeMM]), specifically glucose and linoleic acid, restored lysosomal acidification, TOR activation, and survival with refeeding despite the absence of HLH-30. Worms deficient in lysosomal lipase 2 (lipl-2), a lysosomal enzyme that is transcriptionally up-regulated in starvation in an HLH-30-dependent manner, also demonstrated increased mortality with starvation-refeeding that was partially rescued with glucose, suggesting a critical role for LIPL-2 in lipid metabolism under starvation. CeMM induced transcription of vacuolar proton pump subunits in hlh-30 mutant worms, and knockdown of vacuolar H+-ATPase 12 (vha-12) and its upstream regulator, nuclear hormone receptor 31 (nhr-31), abolished the rescue with CeMM. Loss of Ras-related GTP binding protein C homolog 1 RAGC-1, the ortholog for mammalian RagC/D GTPases, conferred starvation-refeeding lethality, and RAGC-1 overexpression was sufficient to rescue starved hlh-30 mutant worms, demonstrating a critical need for TOR activation with refeeding. These results show that HLH-30 activation is critical for sustaining survival during starvation-refeeding stress via regulating TOR. Glucose and linoleic acid bypass the requirement for HLH-30 in coupling lysosome nutrient sensing to survival.
Volume 17(5)
Pages e3000245
Published 2019-5-1
DOI 10.1371/journal.pbio.3000245
PMID 31086360
PMC PMC6516633
MeSH Animals Basic Helix-Loop-Helix Transcription Factors / metabolism* Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / metabolism* Cell Nucleus / metabolism Citric Acid Cycle Culture Media Energy Metabolism / genetics Feeding Behavior Linoleic Acid / metabolism Lipase / metabolism Lysosomes / metabolism* Metabolome Mutation / genetics Nutrients* Phenotype Proton Pumps / metabolism Starvation / metabolism Stress, Physiological / genetics Survival Analysis Transcriptional Activation / genetics
IF 8.386
Times Cited 1
C.elegans tm1978 tm4324 tm1974 tm1954 tm4498 tm4417