Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes.
Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes.
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DOI：
10.1016/j.cell.2022.05.021
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发表时间：
2022-06-23
期刊：
影响因子：
64.5
通讯作者：
Xu, Haoxing
中科院分区：
文献类型：
--
作者：
Hu, Meiqin;Li, Ping;Wang, Ce;Feng, Xinghua;Geng, Qi;Chen, Wei;Marthi, Matangi;Zhang, Wenlong;Gao, Chenlang;Reid, Whitney;Swanson, Joel;Du, Wanlu;Hume, Richard, I;Xu, Haoxing
溶酶体需要pH 4.5和5.0之间的酸性管腔才能有效地消化大分子。通过V-ATPase产生的质子内流和通过未知的“H+泄漏”途径外流，维持了这种最适pH。在这里，我们证明了TMEM175，帕金森病(PD)的一个遗传危险因素，通过作为溶酶体膜上质子激活的质子选择性通道(LyPAP)来介导溶酶体的“H+泄漏”。超出正常范围的酸化有效地激活了LyPAP，终止了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缺乏可导致溶酶体过度酸化，降低蛋白降解活性，促进体内α-突触核蛋白聚集。突变和pH归一化分析表明，该通道的H+电导是正常溶酶体功能所必需的。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最适pH，从而调节溶酶体的降解和PD的病理。TMEM175是溶酶体生理条件下质子激活的质子通道，介导溶酶体质子外流维持稳定的pH。
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. Hence, modulation of LyPAP by cellular cues may dynamically tune the pH optima of endosomes and lysosomes to regulate lysosomal degradation and PD pathology. TMEM175 is a proton-activated proton channel under lysosomal physiological condition, and mediates the lysosomal proton efflux to maintain a steady-state pH.
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