Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes

Cell. 2022 Jun 23;185(13):2292-2308.e20. doi: 10.1016/j.cell.2022.05.021.

Meiqin Hu ¹, Ping Li ², Ce Wang ³, Xinghua Feng ⁴, Qi Geng ³, Wei Chen ³, Matangi Marthi ⁵, Wenlong Zhang ⁶, Chenlang Gao ³, Whitney Reid ³, Joel Swanson ⁵, Wanlu Du ³, Richard I Hume ³, Haoxing Xu ⁷

Affiliations

1 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. Electronic address: [email protected].
2 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.
3 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 4114 Biological Sciences Building (BSB), 1105 N. University Ave, Ann Arbor, MI 48109, USA.
4 Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China; Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.
5 Department of Microbiology & Immunology, University of Michigan Medical School, 6750 Med Sci II, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.
6 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 4114 Biological Sciences Building (BSB), 1105 N. University Ave, Ann Arbor, MI 48109, USA; College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, China.
7 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 4114 Biological Sciences Building (BSB), 1105 N. University Ave, Ann Arbor, MI 48109, USA. Electronic address: [email protected].

PMID: 35750034 DOI: 10.1016/j.cell.2022.05.021

Abstract

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.

Keywords

Proton channel; acidification; degradation; lysosome; pH optimum.

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