title: The 5'-untranslated region regulates ATF5 mRNA stability via nonsense-mediated mRNA decay in response to environmental stress.
abstract: We previously reported that activating transcription factor 5 (ATF5) mRNA increases in response to amino acid limitation, and that this increase is dependent on mRNA stabilization. The ATF5 gene allows transcription of mRNAs with two alternative 5'-UTRs, 5'-UTRα and 5'-UTRβ, derived from exon 1α and exon 1β. 5'-UTRα contains the upstream open reading frames uORF1 and uORF2. Phosphorylation of eukaryotic initiation factor 2α during the integrated stress response had been previously shown to lead to bypassing of uORF2 translation and production of ATF5 protein. Translation of uORF2 is expected to result in translational termination at a position 125 nucleotides upstream of the exon junction, and this fits the criterion of a nonsense-mediated decay target mRNA. We investigated the potential role of 5'-UTRα in the control of mRNA stabilization, and found that 5'-UTRα reduced the stability of ATF5 mRNA. 5'-UTRα-regulated destabilization of mRNA was suppressed by knockdown of the nonsense-mediated decay factors Upf1 and Upf2. Mutation of the downstream AUG (uAUG2) rendered mRNA refractory to Upf1 and Upf2 knockdown. Moreover, 5'-UTRα-regulated down-regulation was hindered by amino acid limitation and tunicamycin treatment, and stress-induced phosphorylation of eukaryotic initiation factor 2α was involved in stabilization of ATF5 mRNA. These studies show that ATF5 mRNA is a naturally occurring normal mRNA target of nonsense-mediated decay, and provide evidence for linkage between stress-regulated translational regulation and the mRNA decay pathway. This linkage constitutes a mechanism that regulates expression of stress response genes.
authors.affiliation: Laboratory of Environmental Molecular Physiology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Hatano
authors.forename: Mariko
authors.initials: M
authors.lastname: Umemura
authors.forename: Natsumi
authors.initials: N
authors.lastname: Kimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takeda
authors.forename: Haruo
authors.initials: H
authors.lastname: Nakano
authors.forename: Shigeru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
mesh_terms: D020121:5' Untranslated Regions; D051696:Activating Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000596:Amino Acids / Q000172:deficiency; D000818:Animals; D005091:Exons; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007438:Introns; D051379:Mice; D016366:Open Reading Frames; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D059367:RNA Cleavage; D020871:RNA Stability; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D019892:eIF-2 Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; C507532:ATF5 protein, human; D051696:Activating Transcription Factors; D000596:Amino Acids; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C468286:UPF2 protein, human; C435487:UPF3A protein, human; D019892:eIF-2 Kinase
keywords: activating transcription factor 5; eIF2α; nonsense-mediated mRNA decay; stress response; transcription factor; translation