title: Translation from the 5' untranslated region shapes the integrated stress response.
abstract: Translated regions distinct from annotated coding sequences have emerged as essential elements of the proteome. This includes upstream open reading frames (uORFs) present in mRNAs controlled by the integrated stress response (ISR) that show "privileged" translation despite inhibited eukaryotic initiation factor 2-guanosine triphosphate-initiator methionyl transfer RNA (eIF2·GTP·Met-tRNA(i )(Met)). We developed tracing translation by T cells to directly measure the translation products of uORFs during the ISR. We identified signature translation events from uORFs in the 5' untranslated region of binding immunoglobulin protein (BiP) mRNA (also called heat shock 70-kilodalton protein 5 mRNA) that were not initiated at the start codon AUG. BiP expression during the ISR required both the alternative initiation factor eIF2A and non-AUG-initiated uORFs. We propose that persistent uORF translation, for a variety of chaperones, shelters select mRNAs from the ISR, while simultaneously generating peptides that could serve as major histocompatibility complex class I ligands, marking cells for recognition by the adaptive immune system.
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA. Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. shelley@walterlab.ucsf.edu nshastri@berkeley.edu peter@walterlab.ucsf.edu.
authors.forename: Shelley R
authors.initials: SR
authors.lastname: Starck
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: Jordan C
authors.initials: JC
authors.lastname: Tsai
authors.affiliation: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Keling
authors.initials: K
authors.lastname: Chen
authors.affiliation: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Shodiya
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, CA 92521, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Departments of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Kinnosuke
authors.initials: K
authors.lastname: Yahiro
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, CA 92521, USA.
authors.forename: Manuela
authors.initials: M
authors.lastname: Martins-Green
authors.affiliation: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. shelley@walterlab.ucsf.edu nshastri@berkeley.edu peter@walterlab.ucsf.edu.
authors.forename: Nilabh
authors.initials: N
authors.lastname: Shastri
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA. shelley@walterlab.ucsf.edu nshastri@berkeley.edu peter@walterlab.ucsf.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Walter
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D058948:Cell Tracking; D018387:Codon, Initiator / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D016366:Open Reading Frames / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism / Q000382:microbiology / Q000502:physiology
chemical_list: D020121:5' Untranslated Regions; D018387:Codon, Initiator; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D012333:RNA, Messenger
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