Promoter polymorphism rs510432 in ATG5 affects the susceptibility of noise-induced hearing loss by altering the binding of C/EBPβ

Abstract

Noise-induced hearing loss (NIHL) is an occupational-related disease characterized by progressive sensorineural hearing impairment. Autophagy is thought as a key pathway mediated by highly conserved autophagy-related genes (ATGs) and plays a critical role in maintaining the homeostasis of cells, tissue and organisms. However, the potential molecular mechanism linking ATGs with NIHL are still relatively unclear. Here, we conducted a case-control study on 688 NIHL-afflicted cases and 667 normal hearing controls to investigate the relationship of single nucleotide polymorphisms (SNPs) in ATG4C, ATG5 and ATG7 genes with the susceptibility to NIHL. We found that ATG5 rs510432 CT/TT genotypes significantly diminished the risk of NIHL compared to the CC genotype. Individuals with rs510432 CT/TT genotypes had significantly elevated mRNA and plasma levels of ATG5 than those with the CC genotype. Human plasma with the rs510432 CT/TT genotypes expressed obviously higher SOD, GSH-Px and Bcl-2 than that with the CC genotype, while opposite trends were observed for Caspase-3. Mechanistically, rs510432 could regulate the transcription of ATG5 by affecting the binding of C/EBPβ in the promoter region. Of note, C/EBPβ knockdown promoted the expression of ATG5 and LC3-II and simultaneously inhibited p62 expression to induce autophagy in HEI-OC1 cells. Moreover, C/EBPβ knockdown could increase the Bcl-2 expression, but decrease the expressions of Caspase-3, Bax and PARP in HEI-OC1 cells. In summation, our study provides initial evidence that ATG5 rs510432 is associated with the susceptibility to NIHL by altering the binding efficiency of C/EBPβ to ATG5 promoter in a specific allelic manner and it may act as a promising biomarker for NIHL susceptibility.