title: Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation.
abstract: Ribosome stalling during translation has recently been shown to cause neurodegeneration, yet the signaling pathways triggered by stalled elongation complexes are unknown. To investigate these pathways we analyzed the brain of C57BL/6J-Gtpbp2(nmf205)(-/-) mice in which neuronal elongation complexes are stalled at AGA codons due to deficiencies in a tRNA(Arg)UCU tRNA and GTPBP2, a mammalian ribosome rescue factor. Increased levels of phosphorylation of eIF2α (Ser51) were detected prior to neurodegeneration in these mice and transcriptome analysis demonstrated activation of ATF4, a key transcription factor in the integrated stress response (ISR) pathway. Genetic experiments showed that this pathway was activated by the eIF2α kinase, GCN2, in an apparent deacylated tRNA-independent fashion. Further we found that the ISR attenuates neurodegeneration in C57BL/6J-Gtpbp2(nmf205)(-/-) mice, underscoring the importance of cellular and stress context on the outcome of activation of this pathway. These results demonstrate the critical interplay between translation elongation and initiation in regulating neuron survival during cellular stress.
authors.affiliation: Howard Hughes Medical Institute, The Jackson Laboratory for Mammalian Genetics, Bar Harbor, United States.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Ishimura
authors.affiliation: Howard Hughes Medical Institute, The Jackson Laboratory for Mammalian Genetics, Bar Harbor, United States.
authors.forename: Gabor
authors.initials: G
authors.lastname: Nagy
authors.affiliation: Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dotu
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, United States.|Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United States.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Chuang
authors.affiliation: Howard Hughes Medical Institute, The Jackson Laboratory for Mammalian Genetics, Bar Harbor, United States.|Department of Cell and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, United States.|Section of Neurobiology, University of California, La Jolla, United States.
authors.forename: Susan L
authors.identifier: 0000-0002-6740-593X
authors.initials: SL
authors.lastname: Ackerman
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis; D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000172:deficiency; D020869:Gene Expression Profiling; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology; D010441:Peptide Chain Elongation, Translational; D010442:Peptide Chain Initiation, Translational; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D012347:RNA, Transfer, Arg / Q000235:genetics; D012270:Ribosomes / Q000378:metabolism*
chemical_list: C081452:Atf4 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D012347:RNA, Transfer, Arg; D051701:Activating Transcription Factor 4; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D019204:GTP-Binding Proteins; C000590335:GTPBP2 protein, mouse
keywords: chromosomes; genes; mouse; neurodegeneration; neuroscience; translation elongation; translation initiation