Accumulation of mutant proteins in cells can induce proteinopathies and cause functional damage to organs.Recently,the Cingulin(CGN)protein has been shown to maintain the morphology of cuticular plates of inner ear ha...Accumulation of mutant proteins in cells can induce proteinopathies and cause functional damage to organs.Recently,the Cingulin(CGN)protein has been shown to maintain the morphology of cuticular plates of inner ear hair cells and a frameshift mutation in CGN causes autosomal dominant non-syndromic hearing loss.Here,we find that the mutant CGN proteins form insoluble aggregates which accumulate intracellularly and lead to cell death.Expression of the mutant CGN in the inner ear results in severe hair cell death and hearing loss in mice,resembling the auditory phenotype in human patients.Interestingly,a human-specific residue(V1112)in the neopeptide generated by the frameshift mutation is critical for the aggregation and cytotoxicity of the mutant human CGN.Moreover,the expression of heat shock factor 1(HSF1)decreases the accumulation of insoluble mutant CGN aggregates and rescues cell death.In summary,these findings identify mutant-specific toxic polypeptides as a disease-causing mechanism of the deafness mutation in CGN,which can be targeted by the expression of the cell chaperone response regulator HSF1.展开更多
基金supported by the National Natural Science Foundation of China(82171136 and 92368110 to G.W.,82201291 to G.-J.Z.,82171145 to X.Q.,81870721 to J.C.,and 81970884 and 82192862 to X.G.)Natural Science Foundation of Jiangsu Province(BK20220189to G.-J.Z.and BK20220188 to Q.L.)+1 种基金Special Foundation for Health Science and Technology Development of Nanjing(YKK21109 to G.-J.Z.)the Clinical Research Foundation of Drum Tower Hospital affiliated to Nanjing University Medical School(2021-LCYJ-PY-04 to G.-J.Z.)。
文摘Accumulation of mutant proteins in cells can induce proteinopathies and cause functional damage to organs.Recently,the Cingulin(CGN)protein has been shown to maintain the morphology of cuticular plates of inner ear hair cells and a frameshift mutation in CGN causes autosomal dominant non-syndromic hearing loss.Here,we find that the mutant CGN proteins form insoluble aggregates which accumulate intracellularly and lead to cell death.Expression of the mutant CGN in the inner ear results in severe hair cell death and hearing loss in mice,resembling the auditory phenotype in human patients.Interestingly,a human-specific residue(V1112)in the neopeptide generated by the frameshift mutation is critical for the aggregation and cytotoxicity of the mutant human CGN.Moreover,the expression of heat shock factor 1(HSF1)decreases the accumulation of insoluble mutant CGN aggregates and rescues cell death.In summary,these findings identify mutant-specific toxic polypeptides as a disease-causing mechanism of the deafness mutation in CGN,which can be targeted by the expression of the cell chaperone response regulator HSF1.
