Abstract
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.
Original language | English (US) |
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Pages (from-to) | 2524-2539.e7 |
Journal | Molecular cell |
Volume | 83 |
Issue number | 14 |
DOIs | |
State | Published - Jul 20 2023 |
Keywords
- LAMP-1 and LAMP-2
- TMEM175
- lysosomal LAMP proteins
- lysosomal hydrolytic function
- lysosomal pH homeostasis
- lysosome acidification
- risk factor for Parkinson's disease
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology