title: 4E-BP is a target of the GCN2-ATF4 pathway during Drosophila development and aging.
abstract: Reduced amino acid availability attenuates mRNA translation in cells and helps to extend lifespan in model organisms. The amino acid deprivation-activated kinase GCN2 mediates this response in part by phosphorylating eIF2α. In addition, the cap-dependent translational inhibitor 4E-BP is transcriptionally induced to extend lifespan in Drosophila melanogaster, but through an unclear mechanism. Here, we show that GCN2 and its downstream transcription factor, ATF4, mediate 4E-BP induction, and GCN2 is required for lifespan extension in response to dietary restriction of amino acids. The 4E-BP intron contains ATF4-binding sites that not only respond to stress but also show inherent ATF4 activity during normal development. Analysis of the newly synthesized proteome through metabolic labeling combined with click chemistry shows that certain stress-responsive proteins are resistant to inhibition by 4E-BP, and gcn2 mutant flies have reduced levels of stress-responsive protein synthesis. These results indicate that GCN2 and ATF4 are important regulators of 4E-BP transcription during normal development and aging.
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016 mjkang@amc.seoul.kr hyungdon.ryoo@nyumc.org.|Department of Biomedical Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016.
authors.forename: Deepika
authors.identifier: 0000-0003-1930-3549
authors.initials: D
authors.lastname: Vasudevan
authors.affiliation: Department of Biomedical Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
authors.forename: Kwonyoon
authors.identifier: 0000-0002-5232-0896
authors.initials: K
authors.lastname: Kang
authors.affiliation: Proteomics Core Laboratory, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
authors.forename: Kyunggon
authors.identifier: 0000-0002-3072-5331
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016.
authors.forename: Nan
authors.identifier: 0000-0002-4134-7911
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016.
authors.forename: Thomas A
authors.identifier: 0000-0001-7049-2088
authors.initials: TA
authors.lastname: Neubert
authors.affiliation: Department of Biology, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02453.
authors.forename: Michael T
authors.identifier: 0000-0002-7366-7987
authors.initials: MT
authors.lastname: Marr
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016 mjkang@amc.seoul.kr hyungdon.ryoo@nyumc.org.
authors.forename: Hyung Don
authors.identifier: 0000-0002-1046-535X
authors.initials: HD
authors.lastname: Ryoo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000172:deficiency; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D057930:Click Chemistry; D018753:Diet, Protein-Restricted; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D059865:Endoplasmic Reticulum Stress; D005838:Genotype; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007438:Introns; D008136:Longevity; D009154:Mutation; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020543:Proteome; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D000596:Amino Acids; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors; D011494:Protein Kinases; D020543:Proteome; D014157:Transcription Factors; D019892:eIF-2 Kinase; C410006:Thor protein, Drosophila; C512536:crc protein, Drosophila; C585051:GCN2 protein, Drosophila