title: Essential role of eIF5-mimic protein in animal development is linked to control of ATF4 expression.
abstract: Translational control of transcription factor ATF4 through paired upstream ORFs (uORFs) plays an important role in eukaryotic gene regulation. While it is typically induced by phosphorylation of eIF2α, ATF4 translation can be also induced by expression of a translational inhibitor protein, eIF5-mimic protein 1 (5MP1, also known as BZW2) in mammals. Here we show that the 5MP gene is maintained in eukaryotes under strong purifying selection, but is uniquely missing in two major phyla, nematoda and ascomycota. The common function of 5MP from protozoa, plants, fungi and insects is to control translation by inhibiting eIF2. The affinity of human 5MP1 to eIF2β was measured as being equivalent to the published value of human eIF5 to eIF2β, in agreement with effective competition of 5MP with eIF5 for the main substrate, eIF2. In the red flour beetle, Tribolium castaneum, RNA interference studies indicate that 5MP facilitates expression of GADD34, a downstream target of ATF4. Furthermore, both 5MP and ATF4 are essential for larval development. Finally, 5MP and the paired uORFs allowing ATF4 control are conserved in the entire metazoa except nematoda. Based on these findings, we discuss the phylogenetic and functional linkage between ATF4 regulation and 5MP expression in this group of eukaryotes.
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hiraishi
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Oatman
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Haller
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA Arthropod Genomics Center, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Logan
authors.initials: L
authors.lastname: Blunk
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA Arthropod Genomics Center, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Benton
authors.initials: B
authors.lastname: McGivern
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Morris
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Papadopoulos
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA Arthropod Genomics Center, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Wade
authors.initials: W
authors.lastname: Gutierrez
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA Arthropod Genomics Center, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Gordon
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Wahaj
authors.initials: W
authors.lastname: Bokhari
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: David
authors.initials: D
authors.lastname: Miles
authors.affiliation: USDA-ARS, Hard WinterWheat Genetics Research Unit, Kansas State University, Manhattan, KS 66506.
authors.forename: John
authors.initials: J
authors.lastname: Fellers
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Masayo
authors.initials: M
authors.lastname: Asano
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Loubna
authors.initials: L
authors.lastname: Tazi
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rothenburg
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA Arthropod Genomics Center, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Brown
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA kasano@ksu.edu.
authors.forename: Katsura
authors.initials: K
authors.lastname: Asano
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D004268:DNA-Binding Proteins / Q000145:classification / Q000378:metabolism* / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D040061:Eukaryotic Initiation Factor-5 / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D019476:Insect Proteins / Q000378:metabolism; D016366:Open Reading Frames; D010802:Phylogeny; D014176:Protein Biosynthesis; D054645:Protein Phosphatase 1 / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D014231:Tribolium / Q000201:enzymology / Q000235:genetics / Q000254:growth & development
chemical_list: C568809:BZW2 protein, human; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D040061:Eukaryotic Initiation Factor-5; D019476:Insect Proteins; D051701:Activating Transcription Factor 4; D054645:Protein Phosphatase 1