title: Coordinate regulation of eIF2α phosphorylation by PPP1R15 and GCN2 is required during Drosophila development.
abstract: Phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) by the kinase GCN2 attenuates protein synthesis during amino acid starvation in yeast, whereas in mammals a family of related eIF2α kinases regulate translation in response to a variety of stresses. Unlike single-celled eukaryotes, mammals also possess two specific eIF2α phosphatases, PPP1R15a and PPP1R15b, whose combined deletion leads to a poorly understood early embryonic lethality. We report the characterisation of the first non-mammalian eIF2α phosphatase and the use of Drosophila to dissect its role during development. The Drosophila protein demonstrates features of both mammalian proteins, including limited sequence homology and association with the endoplasmic reticulum. Of note, although this protein is not transcriptionally regulated, its expression is controlled by the presence of upstream open reading frames in its 5'UTR, enabling induction in response to eIF2α phosphorylation. Moreover, we show that its expression is necessary for embryonic and larval development and that this is to oppose the inhibitory effects of GCN2 on anabolic growth.
authors: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research (CIMR), Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.
authors: Elke
authors: E
authors: Malzer
authors: Malgorzata
authors: M
authors: Szajewska-Skuta
authors: Lucy E
authors: LE
authors: Dalton
authors: Sally E
authors: SE
authors: Thomas
authors: Nan
authors: N
authors: Hu
authors: Helen
authors: H
authors: Skaer
authors: David A
authors: DA
authors: Lomas
authors: Damian C
authors: DC
authors: Crowther
authors: Stefan J
authors: SJ
authors: Marciniak
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D019556:COS Cells; D002522:Chlorocebus aethiops; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D004625:Embryo, Nonmammalian; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D020121:5' Untranslated Regions; D029721:Drosophila Proteins; D015852:Eukaryotic Initiation Factor-2; C585051:GCN2 protein, Drosophila; D011494:Protein Kinases; C585050:PPP1R15 protein, Drosophila; D054645:Protein Phosphatase 1
keywords: CREP; Development; GADD34; GCN2; eIF2α