Surviving starvation simply without TFEB

Abstract

Starvation is among the most ancient of selection pressures, driving evolution of a robust arsenal of starvation survival defenses. In order to survive starvation stress, organisms must be able to curtail anabolic processes during starvation and judiciously activate catabolic pathways. Although the activation of metabolic defenses in response to nutrient deprivation is an obvious component of starvation survival, less appreciated is the importance of the ability to recover from starvation upon re-exposure to nutrients. In order for organisms to successfully recover from starvation, cells must be kept in a state of ready so that upon the return of nutrients, activities such as growth and reproduction can be resumed. Critical to this state of ready is the lysosome, an organelle that provides essential signals of nutrient sufficiency to cell growth-activating pathways in the fed state. In this issue, Murphy and colleagues provide evidence that exposure of Caenorhabditis elegans roundworms to 2 simple nutrients, glucose and the polyunsaturated fatty acid linoleate, is able to render lysosomal function competent to activate key downstream starvation recovery pathways, bypassing the need for a master transcriptional regulator of lysosomes. These findings provide a quantum leap forward in our understanding of the cellular determinants that permit organisms to survive cycles of feast and famine.

Fig 1. HLH-30/TFEB regulates a complex transcriptional network critical for nutrient sensing and starvation defenses.

In wild-type C. elegans under starvation conditions, HLH-30 activates lysosome biogenesis and catabolic pathways, which encourage starvation survival and prime the animal for recovery from starvation upon re-feeding. Without HLH-30, C. elegans fail to induce lipolytic and lysosomal genes such as lipl-2 and VHA genes, leading to diminished starvation survival and failure to recover from starvation once food is reintroduced. Murphy and colleagues in this edition of PLOS Biology report that simple nutrients glucose and linoleic acid can bypass the need for HLH-30 in recovery from starvation. It remains unknown how glucose and linoleic acid bypass the need for HLH-30 but at least in part it may be through restoration of lysosomal function and mTORC1 activity downstream of HLH-30 action. HLH-30, helix-loop-helix family member 30; mTORC1, mechanistic target of rapamycin complex 1; TFEB, transcription factor EB; VHA, vacuolar H⁺-ATPase.