溶酶体
生物
细胞生物学
平衡
功能(生物学)
生物化学
细胞生理学
甘露糖6-磷酸受体
酶
细胞
作者
Jiyuan Zhang,Weizhong Zeng,Yanping Han,William R. Lee,Jen Liou,Youxing Jiang
出处
期刊:Molecular Cell
[Elsevier]
日期:2023-07-01
卷期号:83 (14): 2524-2539.e7
被引量:14
标识
DOI:10.1016/j.molcel.2023.06.004
摘要
Maintaining a highly acidic lysosomal pH is central to cellular physiology. Here, we use functional proteomics, single-particle cryo-EM, electrophysiology, and in vivo imaging to unravel a key biological function of human lysosome-associated membrane proteins (LAMP-1 and LAMP-2) in regulating lysosomal pH homeostasis. Despite being widely used as a lysosomal marker, the physiological functions of the LAMP proteins have long been overlooked. We show that LAMP-1 and LAMP-2 directly interact with and inhibit the activity of the lysosomal cation channel TMEM175, a key player in lysosomal pH homeostasis implicated in Parkinson's disease. This LAMP inhibition mitigates the proton conduction of TMEM175 and facilitates lysosomal acidification to a lower pH environment crucial for optimal hydrolase activity. Disrupting the LAMP-TMEM175 interaction alkalinizes the lysosomal pH and compromises the lysosomal hydrolytic function. In light of the ever-increasing importance of lysosomes to cellular physiology and diseases, our data have widespread implications for lysosomal biology.
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