TY - JOUR
T1 - XBP1 mitigates aminoglycoside-induced endoplasmic reticulum stress and neuronal cell death
AU - Oishi, N.
AU - Duscha, S.
AU - Boukari, H.
AU - Meyer, M.
AU - Xie, J.
AU - Wei, G.
AU - Schrepfer, T.
AU - Roschitzki, B.
AU - Boettger, E. C.
AU - Schacht, J.
N1 - Funding Information:
Acknowledgements. The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE57198 (http://www.ncbi.nlm.nih.gov/geo/query/ acc.cgi?acc = GSE57198). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD000933 and DOI 10.6019/PXD000933. We thank Ariane Kanicki and the Histology Core at KHRI for valuable help with cochlear histology. We thank Christian Trachsel, Jonas Grossman and Claudia Fortes from the FGCZ proteomics team for technical help and advice, and Christele Thibault and Doulaye Dembele from the Microarray and Sequencing Platform of the IGBMC, Illkirch, France, for help with the microarray analysis. The project was supported by grant R01 DC-003685 and core grant P30 DC-05188 from the National Institute on Deafness and Other Communication Disorders, National Institutes of Health to JS.
Publisher Copyright:
© 2015 Macmillan Publishers Limited All rights reserved 2041-4889/15.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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, glucoseregulated 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.
AB - 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, glucoseregulated 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.
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U2 - 10.1038/cddis.2015.108
DO - 10.1038/cddis.2015.108
M3 - Article
C2 - 25973683
AN - SCOPUS:84970920294
SN - 2041-4889
VL - 6
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 5
M1 - 108
ER -
