Dataset Information

Molecular Determinants of the Regulation of Development and Metabolism by Neuronal eIF2? Phosphorylation in Caenorhabditis 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 ?-subunit of eukaryotic translation initiation factor 2 (eIF2?) 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? phosphorylation on development and physiology of C. elegans Isolation and characterization of mutations in eif-2Ba encoding the ?-subunit of eIF2B support a conserved role, previously established by studies in yeast, for eIF2B? in providing a binding site for phosphorylated eIF2? to inhibit the exchange factor eIF2B catalytic activity that is required for translation initiation. We also identified a mutation in eif-2c, encoding the ?-subunit of eIF2, which confers insensitivity to the effects of phosphorylated eIF2? while also altering the requirement for eIF2B?. In addition, we show that constitutive expression of eIF2? 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? 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? phosphorylation in the ASI sensory neuron pair may modulate internal nutrient sensing and signaling pathways, with corresponding organismal effects on development and metabolism.

SUBMITTER: Kulalert W

PROVIDER: S-EPMC5419473 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular Determinants of the Regulation of Development and Metabolism by Neuronal eIF2α Phosphorylation in <i>Caenorhabditis elegans</i>.

Kulalert Warakorn W Sadeeshkumar Harini H Zhang Ying K YK Schroeder Frank C FC Kim Dennis H DH

Genetics 20170314 1

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 of <i>Caenorhabditis elegans</i> into dauer diapause. Here, we identified and characterized the molecular determinants that confer sensitivity to effects of neuronal eIF2α phosphorylation on d ...[more]

PMID: 28292919

Similar Datasets

Project description:Reactive oxygen species (ROS) are signalling molecules whose study in intact organisms has been hampered by their potential toxicity. This has prevented a full understanding of their role in organismal processes such as development, aging and disease. In Caenorhabditis elegans, the development of the vulva is regulated by a signalling cascade that includes LET-60ras (homologue of mammalian Ras), MPK-1 (ERK1/2) and LIN-1 (an ETS transcription factor). We show that both mitochondrial and cytoplasmic ROS act on a gain-of-function (gf) mutant of the LET-60ras protein through a redox-sensitive cysteine (C118) previously identified in mammals. We show that the prooxidant paraquat as well as isp-1, nuo-6 and sod-2 mutants, which increase mitochondrial ROS, inhibit the activity of LET-60rasgf on vulval development. In contrast, the antioxidant NAC and loss of sod-1, both of which decrease cytoplasmic H202, enhance the activity of LET-60rasgf. CRISPR replacement of C118 with a non-oxidizable serine (C118S) stimulates LET-60rasgf activity, whereas replacement of C118 with aspartate (C118D), which mimics a strongly oxidised cysteine, inhibits LET-60rasgf. These data strongly suggest that C118 is oxidized by cytoplasmic H202 generated from dismutation of mitochondrial and/or cytoplasmic superoxide, and that this oxidation inhibits LET-60ras. This contrasts with results in cultured mammalian cells where it is mostly nitric oxide, which is not found in worms, that oxidizes C118 and activates Ras. Interestingly, PQ, NAC and the C118S mutation do not act on the phosphorylation of MPK-1, suggesting that oxidation of LET-60ras acts on an as yet uncharacterized MPK-1-independent pathway. We also show that elevated cytoplasmic superoxide promotes vulva formation independently of C118 of LET-60ras and downstream of LIN-1. Finally, we uncover a role for the NADPH oxidases (BLI-3 and DUOX-2) and their redox-sensitive activator CED-10rac in stimulating vulva development. Thus, there are at least three genetically separable pathways by which ROS regulates vulval development.

Dataset Information

Molecular Determinants of the Regulation of Development and Metabolism by Neuronal eIF2? Phosphorylation in Caenorhabditis elegans.

Publications

Molecular Determinants of the Regulation of Development and Metabolism by Neuronal eIF2α Phosphorylation in <i>Caenorhabditis elegans</i>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets