Schematic depicting pathways whereby simple nutrients bypass <i>hlh-30</i> to promote survival under starvation conditions.

Under starvation stress, wild-type worms activate hlh-30–dependent expression of target genes such as lipl-2 (a lysosomal lipase) via inducing cytosol to nuclear translocation of HLH-30 (top panel). lipl-2 induction plays a critical role in starvation survival. Refeeding with E. coli OP50 triggers increased ragc-1 transcript levels, which couple nutrient sensing on acidified lysosomes and TOR activation to survival (top panel). In starved hlh-30–deficient worms, lack of HLH-30–induced transcription impairs lipl-2 up-regulation and is accompanied by reduced ragc-1 levels upon refeeding (middle panel). Starved hlh-30–deficient worms demonstrate marked energy deficiency with decreased lysosome abundance, leading to death despite refeeding with E. coli OP50 (middle panel). Refeeding starved hlh-30–deficient worms with CeMM provides simple nutrients, namely glucose and linoleic acid, which restore ATP levels and induce nhr-31–mediated vha gene transcription (bottom panel). CeMM refeeding also restores ragc-1 expression and lysosome acidification and abundance and sustains survival with subsequent E. coli OP50 feeding (bottom panel). Impaired TOR activation with rapamycin treatment and loss of ragc-1 prevent nutrient sensing to TOR upon refeeding following starvation, and rapamycin prevents CeMM rescue in starved hlh-30–deficient worms. Horizontal black arrows indicate causal relation. Horizontal dotted arrows indicate transition from starvation to refeeding. Upward arrows indicate increased levels. Red cross marks indicate absence of the indicated event. CeMM, C. elegans maintenance medium; hlh-30, basic helix–loop–helix transcription factor 30; hlh-30(lf), loss-of-function tm1978 mutation hlh-30; lipl-2, lysosomal lipase 2; nhr-31, nuclear hormone receptor 31; ragc-1, the ortholog for mammalian RagC/D GTPases; TOR, target of rapamycin.