,Trafficking abnormality and ER stress underlie functional deficiency of hearing impairment-associat

• 作 者: Kun Xia Hong Ma Hui Xiong Qian Pan Liangqun Huang Danling Wang Zhuohua Zhang
• 机 构: State Key Laboratory of Medical Genetics,Central South University,Changsha 410083,China“,”Bumham Ins
• 出 处: 蛋白质与细胞
• 发表日期: 2010年10期
• 关键词: gap junction bip inner ear protein folding

Hearing impairment (HI) affects 1/1000 children and over 2% of the aged population.We have previously reported that mutations in the gene encoding gap junction protein connexin-31 (Cx31) are associated with HI.The pathological mechanism of the disease mutations remains unknown.Here,we show that expression of Cx31 in the mouse inner ear is developmentally regulated with a high level in adult inner hair cells and spiral ganglion neurons that are critical for the hearing process.In transfected cells,wild type Cx31 protein (Cx31wt) forms functional gap junction at cell-cell-contacts.In contrast,two Hl-associated Cx31 mutants,Cx31R180X and Cx31E183K resided primarily in the ER and Golgi-like intracellular punctate structures,respectively,and failed to mediate lucifer yellow transfer.Expression of Cx31 mutants but not Cx31wt leads to upregulation of and increased association with the ER chaperone BiP indicating ER stress induction.Together,the Hl-associated Cx31 mutants are impaired in trafficking,promote ER stress,and hence lose the ability to assemble functional gap junctions.The study reveals a potential pathological mechanism of Hl-associated Cx31 mutations.