title: XBP1 mitigates aminoglycoside-induced endoplasmic reticulum stress and neuronal cell death.
abstract: Here we study links between aminoglycoside-induced mistranslation, protein misfolding and neuropathy. We demonstrate that aminoglycosides induce misreading in mammalian cells and assess endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways. Genome-wide transcriptome and proteome analyses revealed upregulation of genes related to protein folding and degradation. Quantitative PCR confirmed induction of UPR markers including C/EBP homologous protein, glucose-regulated protein 94, binding immunoglobulin protein and X-box binding protein-1 (XBP1) mRNA splicing, which is crucial for UPR activation. We studied the effect of a compromised UPR on aminoglycoside ototoxicity in haploinsufficient XBP1 (XBP1(+/-)) mice. Intra-tympanic aminoglycoside treatment caused high-frequency hearing loss in XBP1(+/-) mice but not in wild-type littermates. Densities of spiral ganglion cells and synaptic ribbons were decreased in gentamicin-treated XBP1(+/-) mice, while sensory cells were preserved. Co-injection of the chemical chaperone tauroursodeoxycholic acid attenuated hearing loss. These results suggest that aminoglycoside-induced ER stress and cell death in spiral ganglion neurons is mitigated by XBP1, masking aminoglycoside neurotoxicity at the organismal level.
authors.affiliation: Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: N
authors.initials: N
authors.lastname: Oishi
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Duscha
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Boukari
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: G
authors.initials: G
authors.lastname: Wei
authors.affiliation: 1] Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, USA [2] Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Schrepfer
authors.affiliation: Functional Genomics Center Zurich, ETH Zürich, Universität Zürich, Zürich, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Roschitzki
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: E C
authors.initials: EC
authors.lastname: Boettger
authors.affiliation: Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Schacht
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D005839:Gentamicins / Q000494:pharmacology*; D057809:HEK293 Cells; D006198:Hair Cells, Auditory / Q000473:pathology; D006316:Hearing Loss, High-Frequency / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D009474:Neurons / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D017510:Protein Folding; D057165:Proteostasis Deficiencies; D012326:RNA Splicing / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D013136:Spiral Ganglion / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology; D000071717:X-Box Binding Protein 1
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D004268:DNA-Binding Proteins; D005839:Gentamicins; D008562:Membrane Glycoproteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C053387:endoplasmin; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine