title: Molecular Determinants of the Regulation of Development and Metabolism by Neuronal eIF2α Phosphorylation inCaenorhabditis elegans.
abstract: 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 α-subunit of eukaryotic translation initiation factor 2 (eIF2α) in two chemosensory neurons by PEK-1/PERK promotes entry ofCaenorhabditis elegansinto dauer diapause. Here, we identified and characterized the molecular determinants that confer sensitivity to effects of neuronal eIF2α phosphorylation on development and physiology ofC. elegansIsolation and characterization of mutations ineif-2Baencoding the α-subunit of eIF2B support a conserved role, previously established by studies in yeast, for eIF2Bα in providing a binding site for phosphorylated eIF2α to inhibit the exchange factor eIF2B catalytic activity that is required for translation initiation. We also identified a mutation ineif-2c, encoding the γ-subunit of eIF2, which confers insensitivity to the effects of phosphorylated eIF2α while also altering the requirement for eIF2Bγ. In addition, we show that constitutive expression of eIF2α 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 eIF2α 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 eIF2α phosphorylation in the ASI sensory neuron pair may modulate internal nutrient sensing and signaling pathways, with corresponding organismal effects on development and metabolism.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Warakorn
authors.initials: W
authors.lastname: Kulalert
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Harini
authors.initials: H
authors.lastname: Sadeeshkumar
authors.affiliation: Boyce Thompson Institute, Cornell University, Ithaca, New York 14853.|Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853.
authors.forename: Ying K
authors.initials: YK
authors.lastname: Zhang
authors.affiliation: Boyce Thompson Institute, Cornell University, Ithaca, New York 14853.|Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Schroeder
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 dhkim@mit.edu.
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development; D015852:Eukaryotic Initiation Factor-2 / Q000096:biosynthesis / Q000235:genetics*; D020717:Eukaryotic Initiation Factor-2B / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011984:Sensory Receptor Cells / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D020717:Eukaryotic Initiation Factor-2B
keywords: Caenorhabditis elegans; dauer; eIF2α; phosphorylation; sensory neurons; translational control