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

Hu, Meiru; Li, Ping; Wang, Ce; Feng, Xinghua; Geng, Qi Rong; Chen, Wei; Marthi, Matangi; Zhang, Wenlong; Gao, Chenlang; Reid, Whitney; Swanson, Joel A.; Du, Wanlu; Hume, Richard I.; Xu, Haoxing

doi:10.1016/j.cell.2022.05.021

Cited by 112 publications

(124 citation statements)

References 86 publications

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“…Others are gated by protons acting on the intracellular side of the membrane ( Cuello et al, 2010 ; Wang et al, 2010 ). Notably, the only other plasmalemma proton channel in eukaryotes, the voltage-gated proton channel Hv1, shows a shift in voltage dependence as a function of pH ( Ramsey et al, 2006 ; Decoursey, 2012 ), while a lysosomal K + channel, TMEM175 was recently shown to function as a proton-activated proton channel ( Cang et al, 2015 ; Hu et al, 2022 ; Zheng et al, 2022 ). For channels in which the proton is not the primary permeant ion, the effect of pH on gating can be measured simply by comparing current magnitudes as extracellular pH is varied.…”

Section: Discussionmentioning

confidence: 99%

Structural motifs for subtype-specific pH-sensitive gating of vertebrate otopetrin proton channels

Teng

Kaplan

Liang

et al. 2022

eLife

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Otopetrin (OTOP) channels are proton-selective ion channels conserved among vertebrates and invertebrates, with no structural similarity to other ion channels. There are three vertebrate OTOP channels (OTOP1, OTOP2, and OTOP3), of which one (OTOP1) functions as a sour taste receptor. Whether extracellular protons gate OTOP channels, in addition to permeating them, was not known. Here, we compare the functional properties of the three murine OTOP channels using patch-clamp recording and cytosolic pH microfluorimetry. We find that OTOP1 and OTOP3 are both steeply activated by extracellular protons, with thresholds of pHo <6.0 and 5.5, respectively, and kinetics that are pH-dependent. In contrast, OTOP2 channels are broadly active over a large pH range (pH 5 pH 10) and carry outward currents in response to extracellular alkalinization (>pH 9.0). Strikingly, we could change the pH-sensitive gating of OTOP2 and OTOP3 channels by swapping extracellular linkers that connect transmembrane domains. Swaps of extracellular linkers in the N domain, comprising transmembrane domains 1–6, tended to change the relative conductance at alkaline pH of chimeric channels, while swaps within the C domain, containing transmembrane domains 7–12, tended to change the rates of OTOP3 current activation. We conclude that members of the OTOP channel family are proton-gated (acid-sensitive) proton channels and that the gating apparatus is distributed across multiple extracellular regions within both the N and C domains of the channels. In addition to the taste system, OTOP channels are expressed in the vertebrate vestibular and digestive systems. The distinct gating properties we describe may allow them to subserve varying cell-type specific functions in these and other biological systems.

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Section: Discussionmentioning

confidence: 99%

Structural motifs for subtype-specific pH-sensitive gating of vertebrate otopetrin proton channels

Teng

Kaplan

Liang

et al. 2022

eLife

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“…3H ); enrichment of autophagy markers ( Fig. 3I ); and alterations to lysosomal solute channels that regulate transmembrane transport to maintain lysosomal homeostasis, including CLCN7, a key Cl - /H + antiporter that balances charge within the lysosomal lumen 38 , and TMEM175, recently linked to Parkinson’s disease 39 ( Fig. 3J ).…”

Section: Resultsmentioning

confidence: 99%

“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted September 15, 2022. ; https://doi.org/10.1101/2022.09. 13.507260 doi: bioRxiv preprint alterations to lysosomal solute channels that regulate transmembrane transport to maintain lysosomal homeostasis, including CLCN7, a key Cl -/H + antiporter that balances charge within the lysosomal lumen 38 , and TMEM175, recently linked to Parkinson's disease 39 (Fig. 3J).…”

Section: B)mentioning

confidence: 99%

Multiomic Approach Characterises the Neuroprotective Role of Retromer in Regulating Lysosomal Health

Daly

Danson

Lewis

et al. 2022

Preprint

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Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling late-stage maturation of the endo-lysosomal network. Retromer dysfunction, which is linked to neurodegenerative disorders including Parkinson and Alzheimer diseases, manifests in complex cellular phenotypes, though the precise nature of this dysfunction, and its relation to neurodegeneration, remain unclear. Here, we perform the first integrated multiomics approach to provide precise insight into the impact of Retromer dysfunction on endo-lysosomal health and homeostasis within a human neuroglioma cell model. We quantify profound changes to the lysosomal proteome, indicative of broad lysosomal dysfunction and inefficient autophagic lysosome reformation, coupled with a reconfigured cell surface proteome and secretome reflective of increased lysosomal exocytosis. Through this global proteomic approach and parallel transcriptomic analysis, we provide an unprecedented integrated view of Retromer function in regulating lysosomal homeostasis and emphasise its role in neuroprotection.

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“…Lysosomal H + release is proposed to regulate sorting such as ESCRT-dependent inward budding and formation of intraluminal vesicles, as well as mobility and membrane trafficking of lysosomes ( Li et al, 2019 ; Luzio et al, 2007b ). Luminal H + also regulates the activities of various lysosomal ion channels ( Cang et al, 2014 ; Hu et al, 2022 ; Li et al, 2019 ; Xu et al, 2007 ). Because inhibition of V-ATPase leads to rapid lysosomal de-acidification, there must exist an unidentified proton leak conductance (LysoH) on lysosomal membranes ( Christensen et al, 2002 ; Xiong and Zhu, 2016 ; Xu and Ren, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

“…Because inhibition of V-ATPase leads to rapid lysosomal de-acidification, there must exist an unidentified proton leak conductance (LysoH) on lysosomal membranes ( Christensen et al, 2002 ; Xiong and Zhu, 2016 ; Xu and Ren, 2015 ). Because the LysoH current is absent in TMEM175 KO cells, but dramatically increased upon TMEM175 overexpression, TMEM175 is likely the molecular basis of LysoH ( Hu et al, 2022 ; Zheng et al, 2022 ). Acting as a proton-activated proton channel (LyPAP), TMEM175 may regulate the lysosomal pH set-point and optimum to prevent lysosomal over-acidification ( Hu et al, 2022 ; Zheng et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Lysosomal solute and water transport

Zhou

Cai

et al. 2022

Journal of Cell Biology

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Lysosomes mediate hydrolase-catalyzed macromolecule degradation to produce building block catabolites for reuse. Lysosome function requires an osmo-sensing machinery that regulates osmolytes (ions and organic solutes) and water flux. During hypoosmotic stress or when undigested materials accumulate, lysosomes become swollen and hypo-functional. As a membranous organelle filled with cargo macromolecules, catabolites, ions, and hydrolases, the lysosome must have mechanisms that regulate its shape and size while coordinating content exchange. In this review, we discussed the mechanisms that regulate lysosomal fusion and fission as well as swelling and condensation, with a focus on solute and water transport mechanisms across lysosomal membranes. Lysosomal H+, Na+, K+, Ca2+, and Cl− channels and transporters sense trafficking and osmotic cues to regulate both solute flux and membrane trafficking. We also provide perspectives on how lysosomes may adjust the volume of themselves, the cytosol, and the cytoplasm through the control of lysosomal solute and water transport.

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

Cited by 112 publications

References 86 publications

Structural motifs for subtype-specific pH-sensitive gating of vertebrate otopetrin proton channels

Structural motifs for subtype-specific pH-sensitive gating of vertebrate otopetrin proton channels

Multiomic Approach Characterises the Neuroprotective Role of Retromer in Regulating Lysosomal Health

Lysosomal solute and water transport

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