溶酶体
内体
生物
细胞生物学
生物化学
质子泵
甘露糖6-磷酸受体
ATP酶
生物物理学
酶
细胞内
作者
Meiru Hu,Ping Li,Ce Wang,Xinghua Feng,Qi Geng,Wei Chen,Matangi Marthi,Wenlong Zhang,Chenlang Gao,Whitney Reid,Joel A. Swanson,Wanlu Du,Richard I. Hume,Haoxing Xu
出处
期刊:Cell
[Elsevier]
日期:2022-06-01
卷期号:185 (13): 2292-2308.e20
被引量:69
标识
DOI:10.1016/j.cell.2022.05.021
摘要
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.
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