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: N Oishi, S Duscha, H Boukari, M Meyer, J Xie, G Wei, T Schrepfer, B Roschitzki, E C Boettger, J Schacht
• Journal: Cell death & disease (Cell Death Dis) Vol. 6 Pg. e1763 (May 14 2015) ISSN: 2041-4889 [Electronic] England
• PMID: 25973683 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CCAAT-Enhancer-Binding Proteins
• CEBPA protein, human
• DNA-Binding Proteins
• Gentamicins
• Membrane Glycoproteins
• Regulatory Factor X Transcription Factors
• Transcription Factors
• X-Box Binding Protein 1
• XBP1 protein, human
• Xbp1 protein, mouse
• endoplasmin
• Taurochenodeoxycholic Acid
• ursodoxicoltaurine

Topics

• Animals
• CCAAT-Enhancer-Binding Proteins (metabolism)
• Cell Line
• DNA-Binding Proteins (genetics, metabolism)
• Endoplasmic Reticulum (pathology)
• Endoplasmic Reticulum Stress (drug effects)
• Female
• Gentamicins (pharmacology)
• HEK293 Cells
• Hair Cells, Auditory (pathology)
• Hearing Loss, High-Frequency (chemically induced, genetics, pathology)
• Humans
• Male
• Membrane Glycoproteins (metabolism)
• Mice
• Mice, Inbred CBA
• Neurons (pathology)
• Protein Biosynthesis (drug effects)
• Protein Folding
• Proteostasis Deficiencies
• RNA Splicing (genetics)
• Regulatory Factor X Transcription Factors
• Spiral Ganglion (cytology, drug effects, pathology)
• Taurochenodeoxycholic Acid (pharmacology)
• Transcription Factors (genetics, metabolism)
• Unfolded Protein Response (genetics, physiology)
• X-Box Binding Protein 1