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Title: Essential role of eIF5-mimic protein in animal development is linked to control of ATF4 expression

Author
item HIRALSHI, HIROYUKI - Kansas State University
item OATMIN, JAMIE - Kansas State University
item BLUNK, LOGAN - Kansas State University
item GUTIERREZ, WADE - Kansas State University
item Fellers, John
item GORDON, MICHELLE - Kansas State University
item BOKHARI, WAHAJ - Kansas State University
item IKEDA, YUKA - Kansas State University
item MILES, DAVID - Kansas State University
item ASANO, MASAYO - Kansas State University
item TAZI, LOUBNA - Kansas State University
item ROTHENBURG, STEFAN - Kansas State University
item BROWN, SUSAN - Kansas State University
item ASANO, KATSURA - Kansas State University

Submitted to: Nucleic Acids Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/12/2014
Publication Date: 8/21/2014
Publication URL: http://www.nar.oxfordjournals.org/content/42/16/10321.full.pdf+html
Citation: Hiralshi, H., Oatmin, J., Blunk, L., Gutierrez, W., Fellers, J.P., Gordon, M., Bokhari, W., Ikeda, Y., Miles, D., Asano, M., Tazi, L., Rothenburg, S., Brown, S.J., Asano, K. 2014. Essential role of eIF5-mimic protein in animal development is linked to control of ATF4 expression. Nucleic Acids Research. 42(16):10321-10330.

Interpretive Summary: Each organism has specialized methods for controlling genes. Genes are transcribed into RNA, RNA is translated into proteins, and finally the proteins have an assigned function. At each point there are differing types of control. Some genes are controlled at transcription, others are controlled by how their RNA is processed and then proteins can be modified at their individual amino acids, which in turn, affect the protein function. The work reported here describes a protein that controls translation and how it is conserved in many multi-celled organisms. eIF5-mimic protein 1 (5MP1) competes with elF2 for a binding site on RNA. The research isolated 5MP1 from several organisms, including wheat, wheat leaf rust, red flour beetle, and Giardia. 5MP1 has the same function in all of the organisms and can be used to replace a mutant 5MP1 in yeast. In red flour beetle, 5MP1 is important for development. This suggests that the 5MP1 is necessary for the specific organism. However, there are other organisms that have evolved without 5MP1. Overall, the work shows that 5MP1 has been kept in the genome of many organisms, and its function is similar.

Technical Abstract: Translational control of ATF4 through upstream ORFs (uORFs) plays an important role in eukaryotic gene regulation. While ATF4 translation is typically induced by inhibitory phosphorylation of eIF2, ATF4 translation can be also induced by expression of a new translational inhibitor protein, eIF5-mimic protein 1 (5MP1, also known as BZW2) in mammals, which inhibits eIF2 through a direct competition mechanism. Here we show that 5MP gene is maintained in eukaryotes under strong purifying selection, but is uniquely missing in two major groups, Nematoda and Ascomycota. The common function of 5MP from diverse eukaryotes, G. intestinalis, wheat, 9 Basidiomycete fungus and beetle, is to control translation by inhibiting eIF2. In the red flour beetle, Tribolium castaneum, 5MP is essential for larval development and promotes GADD34 expression possibly through ATF4. Since 5MP and uORFs required for ATF4 control are conserved in the entire Metazoa except nematodes, ATF4 regulation may be the specialized role 5MP plays in this group of eukaryotes.