Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 4114 Biological Sciences Building (BSB), 1105 N. University Ave, Ann Arbor, MI 48109, USA; Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 4114 Biological Sciences Building (BSB), 1105 N. University Ave, Ann Arbor, MI 48109, USA; Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
Cell. 2022 Jun 23;185(13):2292-2308.e20. doi: 10.1016/j.cell.2022.05.021.
Lysosomes require an acidic lumen between pH 4.5 and 5.0 for effective digestion of macromolecules. This pH optimum is maintained by proton influx produced by the V-ATPase and efflux through an unidentified "H leak" pathway. Here we show that TMEM175, a genetic risk factor for Parkinson's disease (PD), mediates the lysosomal H leak by acting as a proton-activated, proton-selective channel on the lysosomal membrane (LyPAP). Acidification beyond the normal range potently activated LyPAP to terminate further acidification of lysosomes. An endogenous polyunsaturated fatty acid and synthetic agonists also activated TMEM175 to trigger lysosomal proton release. TMEM175 deficiency caused lysosomal over-acidification, impaired proteolytic activity, and facilitated α-synuclein aggregation in vivo. Mutational and pH normalization analyses indicated that the channel's H conductance is essential for normal lysosome function. Thus, modulation of LyPAP by cellular cues may dynamically tune the pH optima of endosomes and lysosomes to regulate lysosomal degradation and PD pathology.
溶酶体需要 pH4.5 到 5.0 之间的酸性内腔才能有效地消化大分子。这种 pH 最佳值是通过 V-ATPase 产生的质子内流和通过未鉴定的“质子泄漏”途径流出来维持的。在这里，我们表明，帕金森病 (PD) 的遗传风险因素 TMEM175 通过在溶酶体膜上作为质子激活的质子选择性通道（LyPAP）来介导溶酶体的质子泄漏。超出正常范围的酸化强烈激活 LyPAP，以终止溶酶体的进一步酸化。内源性多不饱和脂肪酸和合成激动剂也激活 TMEM175 以触发溶酶体质子释放。TMEM175 缺乏导致溶酶体过度酸化、蛋白酶活性受损，并促进体内α-突触核蛋白聚集。突变和 pH 正常化分析表明，通道的 H 电导对于正常溶酶体功能是必需的。因此，细胞信号对 LyPAP 的调节可能会动态调节内体和溶酶体的 pH 最佳值，以调节溶酶体降解和 PD 病理学。
