Molecular Determinants of the Regulation of Development and Metabolism by Neuronal eIF2α Phosphorylation in Caenorhabditis elegans

Cell-nonautonomous effects of signaling in the nervous system of animals can influence diverse aspects of organismal physiology. We previously showed that phosphorylation of Ser49 of the alpha-subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) in two chemosensory neurons by PEK-1/PERK promotes entry of Caenorhabditis elegans into dauer diapause. Here, we identified and characterized the molecular determinants that confer sensitivity to effects of neuronal eIF2 alpha phosphorylation on development and physiology of C. elegans. Isolation and characterization of mutations in eif-2Ba encoding the alpha-subunit of eIF2B support a conserved role, previously established by studies in yeast, for eIF2B alpha in providing a binding site for phosphorylated eIF2 alpha to inhibit the exchange factor eIF2B catalytic activity that is required for translation initiation. We also identified a mutation in eif-2c, encoding the g-subunit of eIF2, which confers insensitivity to the effects of phosphorylated eIF2 alpha while also altering the requirement for eIF2B gamma. In addition, we show that constitutive expression of eIF2 alpha carrying a phosphomimetic S49D mutation in the ASI pair of sensory neurons confers dramatic effects on growth, metabolism, and reproduction in adult transgenic animals, phenocopying systemic responses to starvation. Furthermore, we show that constitutive expression of eIF2 alpha carrying a phosphomimetic S49D mutation in the ASI neurons enhances dauer entry through bypassing the requirement for nutritionally deficient conditions. Our data suggest that the state of eIF2 alpha phosphorylation in the ASI sensory neuron pair may modulate internal nutrient sensing and signaling pathways, with corresponding organismal effects on development and metabolism.