Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA.
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University/University of Georgia Medical Partnership, Athens, GA 30602, USA.
Sci Adv. 2022 Apr 8;8(14):eabk0942. doi: 10.1126/sciadv.abk0942.
Lysosomes contribute to cellular homeostasis via processes including macromolecule degradation, nutrient sensing, and autophagy. Defective proteins related to lysosomal macromolecule catabolism are known to cause a range of lysosomal storage diseases; however, it is unclear whether mutations in proteins involved in homeostatic nutrient sensing mechanisms cause syndromic sensory disease. Here, we show that SLC7A14, a transporter protein mediating lysosomal uptake of cationic amino acids, is evolutionarily conserved in vertebrate mechanosensory hair cells and highly expressed in lysosomes of mammalian cochlear inner hair cells (IHCs) and retinal photoreceptors. Autosomal recessive mutation of caused loss of IHCs and photoreceptors, leading to presynaptic auditory neuropathy and retinitis pigmentosa in mice and humans. Loss-of-function mutation altered protein trafficking and increased basal autophagy, leading to progressive cell degeneration. This study implicates autophagy-lysosomal dysfunction in syndromic hearing and vision loss in mice and humans.
溶酶体通过大分子降解、营养感应和自噬等过程有助于细胞内稳态。已知与溶酶体大分子分解代谢相关的缺陷蛋白会导致一系列溶酶体贮积症；然而，尚不清楚参与稳态营养感应机制的蛋白质突变是否会导致综合征性感觉疾病。在这里，我们表明，SLC7A14 是一种介导溶酶体摄取阳离子氨基酸的转运蛋白，在脊椎动物机械敏感毛细胞中具有进化保守性，在哺乳动物耳蜗内毛细胞 (IHC) 和视网膜光感受器的溶酶体中高度表达。常染色体隐性突变导致 IHC 和光感受器丧失，导致小鼠和人类出现突触前听觉神经病和视网膜色素变性。功能丧失性突变改变了蛋白质的运输，并增加了基础自噬，导致进行性细胞退化。这项研究表明，自噬溶酶体功能障碍与小鼠和人类的综合征性听力和视力丧失有关。
