Affinage

TMEM175

Endosomal/lysosomal proton channel TMEM175 · UniProt Q9BSA9

Length
504 aa
Mass
55.6 kDa
Annotated
2026-06-10
38 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM175 is a non-canonical lysosomal and endosomal cation channel that sets the ionic and pH environment of the late endo-lysosomal system and thereby controls autophagy, organelle catabolism, and protein quality control (PMID:26317472, PMID:28193887). Rather than the canonical TVGYG selectivity filter, it uses a novel architecture — a homodimer of two 6-transmembrane repeats in eukaryotes (a tetramer in prokaryotes) — in which TM1 lines an hourglass-shaped pore, and layers of hydrophobic isoleucine residues simultaneously form the gate and the K+ selectivity constriction; threonine and serine layers add to selectivity and confer sensitivity to 4-aminopyridine and Zn2+, and channel opening occurs through iris-like helical motions that relocate the gate and expose the filter (PMID:28723891, PMID:32228865, PMID:32267231, PMID:35608336). K+ and Na+ permeation is governed by ion-dehydration energetics through the narrow constriction rather than a structured filter, explaining selectivity in the absence of a P-loop (PMID:35608336). The channel maintains lysosomal membrane potential and luminal pH stability; loss of function destabilizes lysosomal pH, reduces cathepsin and glucocerebrosidase activity, impairs autophagosome-lysosome fusion and autophagic clearance, and depresses mitochondrial respiration, with the predominant pH consequence in challenged cells being alkalinization consistent with K+ conductance (PMID:26317472, PMID:28193887, PMID:41134537). These defects drive accumulation of phosphorylated, detergent-insoluble α-synuclein, and TMEM175 deficiency or the common p.M393T risk variant — which destabilizes the protein and reduces both K+ and proton permeation — link the channel to Parkinson's disease pathogenesis (PMID:28193887, PMID:31261387, PMID:35333573, PMID:36609826). TMEM175 activity is regulated by Akt/PKB and dynamin-dependent endocytosis and is inhibited by Bcl-2 binding, coupling channel gating to survival signaling and mitochondrial homeostasis (PMID:35913019, PMID:34638858). Beyond neurons, TMEM175 governs lysosomal pH in macrophages, where its loss triggers NLRP3 inflammasome activation via cathepsin B leakage, and supports osteoblast differentiation and cardiomyocyte lysosomal function through TFEB-dependent biogenesis (PMID:35913019, PMID:41690940, PMID:39426687, PMID:41741766). Whether TMEM175 additionally functions as a proton-selective channel mediating a major lysosomal H+ leak is actively debated: direct proton-conduction with H57 as a luminal proton-sensing gating residue has been reported (PMID:35750034, PMID:41533442), while rigorous quantitative re-examination found K+ to be the predominant conducted ion and the native H+ leak negligible (PMID:41134537).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2015 High

    Established the founding identity of TMEM175 as the major lysosomal/endosomal K+ channel and tied it to a basic organelle function, answering whether an uncharacterized membrane protein carried lysosomal K+ conductance.

    Evidence Direct lysosomal patch-clamp with genetic knockout plus pH and autophagy assays

    PMID:26317472

    Open questions at the time
    • Molecular basis of selectivity without a GYG filter unresolved
    • Channel structure unknown
    • Physiological gating cues not defined
  2. 2017 High

    Connected channel loss to a defined disease-relevant cascade, showing that TMEM175 deficiency degrades lysosomal proteolysis, GCase activity, and mitochondrial respiration and sensitizes neurons to α-synuclein pathology.

    Evidence shRNA knockdown in neurons with pH, cathepsin, GCase, Seahorse, and phospho-α-syn readouts

    PMID:28193887

    Open questions at the time
    • Causal chain from pH change to α-syn aggregation not dissected
    • In vivo relevance untested at this stage
  3. 2017 High

    Solved the first structure, revealing a unique tetrameric architecture with TM1-lined pore and hydrophobic isoleucine selectivity layers — explaining how a channel selects K+ without a canonical filter.

    Evidence X-ray crystallography of prokaryotic CmTMEM175 with mutagenesis and electrophysiology

    PMID:28723891

    Open questions at the time
    • Prokaryotic; human dimeric architecture not yet confirmed
    • Open vs closed states not both captured
  4. 2019 High

    Characterized the common p.M393T Parkinson's risk variant mechanistically, showing intermediate loss of pH regulation, reduced GCase, and increased α-syn phosphorylation, linking a genetic risk allele to channel dysfunction.

    Evidence Variant overexpression, knockdown specificity, pH/localization assays, computational modeling, patient GCase cohort

    PMID:31261387 PMID:31658403

    Open questions at the time
    • Discordant reports on whether localization is affected
    • Quantitative effect on conductance not measured here
  5. 2020 High

    Defined the human channel in open and closed states and pinpointed the isoleucine gate and selectivity constriction plus threonine/serine selectivity layers and pharmacological sensitivities, providing an atomic gating model.

    Evidence Cryo-EM and X-ray structures of human and bacterial channel with bound ions, mutagenesis, and electrophysiology

    PMID:32228865 PMID:32267231

    Open questions at the time
    • Energetics of selectivity not quantified
    • Physiological gating trigger in lysosome unclear
  6. 2020 Medium

    Extended the lysosomal dysfunction phenotype to mitophagy and ischemic injury, showing TMEM175 deficiency impairs damaged-mitochondria clearance and that overexpression rescues OGD/R-induced lysosomal failure.

    Evidence pH, cathepsin assays, gain/loss of function in neurons and MCAO/R model

    PMID:32799888

    Open questions at the time
    • Single lab
    • Direct link between channel conductance and mitophagy unresolved
  7. 2021 Medium

    Identified upstream regulation by Akt/PKB signaling and dynamin-dependent endocytosis, explaining how channel surface density and activity are dynamically controlled.

    Evidence Two-electrode voltage clamp in oocytes, dominant-negative dynamin, surface immunocytochemistry, Akt pharmacology

    PMID:34638858

    Open questions at the time
    • Direct Akt phosphorylation site not mapped here
    • Oocyte/plasma-membrane context differs from lysosome
  8. 2022 High

    Proposed a second permeation function — proton-activated, proton-selective conductance mediating the lysosomal H+ leak that prevents over-acidification — reframing TMEM175 as a pH-protective channel.

    Evidence Lysosomal patch-clamp, ion substitution, mutagenesis, PUFA/agonist activation, in vivo α-syn model

    PMID:35750034

    Open questions at the time
    • Magnitude of physiological H+ leak contested
    • Reconciliation with predominant K+ conductance unresolved
  9. 2022 High

    Showed K+ and protons share one permeation pathway with pH-dependent structural switching, and that M393T reduces both conductances, unifying the K+ and H+ activities in a single pore.

    Evidence Cryo-EM, whole-endolysosome patch-clamp, MD simulation, mutagenesis

    PMID:35333573

    Open questions at the time
    • Relative physiological contribution of each ion not settled
  10. 2022 High

    Resolved the biophysical basis of K+-over-Na+ selectivity as dehydration energetics assisted by a favorable electrostatic field, explaining selectivity without a structured filter.

    Evidence Higher-resolution cryo-EM, extensive MD simulation, mutagenesis, electrophysiology

    PMID:35608336

    Open questions at the time
    • In situ ionic conditions modeled, not directly measured
  11. 2022 High

    Identified Bcl-2 as a direct inhibitory binding partner and embedded TMEM175 in a ROS/apoptosis feedback loop, and showed knockout is protective in an MPTP Parkinson's model.

    Evidence Co-IP, lysosomal patch-clamp, Bcl-2 inhibitors, ROS/mitophagy assays, TMEM175 KO MPTP mouse

    PMID:35913019

    Open questions at the time
    • Bcl-2 binding interface not mapped structurally
    • Direction of net Parkinson's effect (loss vs gain) context-dependent
  12. 2022 High

    Mapped the binding site and voltage-dependent block mechanism of the classic inhibitor 4-aminopyridine within the open pore.

    Evidence Cryo-EM of inhibitor-bound channel with MD simulations

    PMID:36279431

    Open questions at the time
    • Therapeutic selectivity not addressed
  13. 2023 Medium

    Characterized a panel of PD-patient mutations as loss-of-K+-conductance alleles with reduced Akt affinity and downstream autophagic/UPR defects, strengthening the genetic-functional link to Parkinson's.

    Evidence Patch-clamp, TMEM175-Akt co-IP, autophagic flux and UPR markers in patient fibroblasts

    PMID:36609826

    Open questions at the time
    • Single lab
    • Causality of UPR vs lysosomal defect not separated
  14. 2023 Medium

    Quantified asymmetric bidirectional H+ flux and a high PH/PK permeability ratio, and showed cytosolic-side (not luminal-side) pH and LAMP1 glycosylation modulate conductance.

    Evidence Whole-endolysosome and solid-supported-membrane electrophysiology with loss-of-function mutants and pharmacology

    PMID:37165739 PMID:37628970

    Open questions at the time
    • High PH/PK ratio later contested by quantitative leak measurements
    • LAMP1 modulation mechanism unclear
  15. 2024 High

    Established TMEM175 as a tractable drug target, defining cryo-EM-resolved pore-blocker sites whose acute inhibition paradoxically accelerates lysosomal catabolism and macropinocytosis.

    Evidence Cryo-EM of 2-PPA/AP-6-bound states with catabolism and macropinocytosis assays

    PMID:39116214

    Open questions at the time
    • Mechanism by which channel block enhances catabolism not fully explained
  16. 2024 Medium

    Extended the channel's roles beyond neurons, showing TMEM175 is required for osteoblast differentiation and for an antitoxin compound's endosomal action, demonstrating tissue-broad lysosomal/endosomal functions.

    Evidence Knockdown/4-AP in BMSCs with differentiation and autophagy assays; organelle patch-clamp EC50 and depletion with trafficking assays for DABMA

    PMID:39097908 PMID:39426687

    Open questions at the time
    • Single labs
    • Direct molecular link between channel activity and differentiation/trafficking phenotypes incomplete
  17. 2025 High

    Rigorously re-examined the proton hypothesis and concluded TMEM175 predominantly conducts K+ with a negligible native H+ leak, and that deficiency causes alkalinization rather than over-acidification — directly challenging the proton-channel model.

    Evidence Quantitative lysosomal patch-clamp, pH measurement, genetic manipulation, ion substitution

    PMID:41134537

    Open questions at the time
    • Reconciliation with prior proton-conduction structural/electrophysiology reports unresolved
    • Conditions under which H+ conductance becomes relevant undefined
  18. 2025 High

    Identified luminal H57 as a proton-sensing gating residue forming salt bridges that stabilize the open state, providing a structural mechanism for proton-dependent gating.

    Evidence H57Y mutagenesis, MD simulations, whole-cell and lysosomal patch-clamp, reversal-potential measurements

    PMID:41533442

    Open questions at the time
    • Physiological relevance of proton gating debated given small native leak
    • Does not resolve K+ vs H+ predominance controversy
  19. 2025 High

    Captured agonist-bound open states and defined activation determinants, demonstrating that small-molecule activators can restore PD-variant function and clear pathological α-synuclein in neurons — a therapeutic proof of concept.

    Evidence Cryo-EM with SPR, mutagenesis (T119/H449), patch-clamp, MD, and α-syn clearance assays; pharmacological characterization of CysLT antagonist activators

    PMID:40865534 PMID:41670588

    Open questions at the time
    • In vivo efficacy of agonists not established here
    • Relationship of activation to K+ vs H+ conductance not fully resolved
  20. 2025 High

    Defined an immune and inflammatory role: macrophage TMEM175 loss activates the NLRP3 inflammasome via cathepsin B leakage, promoting anti-tumor immunity, while channel activity restrains silica-induced inflammation through lysosomal pH control.

    Evidence Conditional macrophage KO tumor models, BMDM inflammasome/cross-presentation/cathepsin B assays; BK-/- BMDM with inhibitor and IL-1β readouts

    PMID:40402504 PMID:41690940

    Open questions at the time
    • Whether immune effects derive from K+ or H+ conductance unclear
    • Therapeutic window between neuroprotection and inflammasome activation undefined
  21. 2026 Medium

    Linked TMEM175 to cardiac protection via a lysosome-mTORC1-TFEB biogenesis axis, showing channel restoration reverses post-infarction lysosomal failure.

    Evidence Gain/loss of function in MI and hypoxia models with mTORC1 phosphorylation, TFEB translocation, and autophagic flux readouts

    PMID:41741766

    Open questions at the time
    • Single lab
    • Direct coupling of channel conductance to mTORC1/TFEB not mechanistically resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved whether and under what physiological conditions TMEM175's proton conductance constitutes a functionally significant lysosomal H+ leak versus being a minor consequence of a fundamentally K+-conducting channel.
  • Quantitative native H+ leak magnitude disputed
  • Conditions that switch the channel between ion modes undefined
  • Which conductance drives each disease phenotype unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0005198 structural molecule activity 4 GO:0140299 molecular sensor activity 2
Localization
GO:0005764 lysosome 4 GO:0005768 endosome 2
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-1643685 Disease 3 R-HSA-382551 Transport of small molecules 3 R-HSA-168256 Immune System 2
Partners
AKT1BCL2

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 TMEM175 forms a major K+-selective channel (KEL) on endosomes and lysosomes. Direct lysosomal patch-clamp recordings showed that lysosomes lacking TMEM175 exhibit no K+ conductance, have markedly depolarized membrane potential, little sensitivity to changes in [K+], and compromised luminal pH stability and abnormal fusion with autophagosomes during autophagy. Unlike canonical K+ channels, TMEM175 has two repeats of 6-transmembrane-spanning segments and lacks the GYG P-loop selectivity filter. Direct organelle patch-clamp electrophysiology; genetic knockout; lysosomal pH and autophagy assays Cell High 26317472
2017 TMEM175 deficiency results in unstable lysosomal pH, decreased lysosomal catalytic activity, decreased glucocerebrosidase activity, impaired autophagosome clearance, and decreased mitochondrial respiration. In rat primary neurons, TMEM175 deficiency increased susceptibility to exogenous α-synuclein fibrils and caused increased phosphorylated and detergent-insoluble α-synuclein deposits. shRNA knockdown in neuronal model; lysosomal pH assays; cathepsin activity assays; GCase activity assay; mitochondrial respiration (Seahorse); α-synuclein fibril treatment with phospho-α-syn immunostaining Proceedings of the National Academy of Sciences of the United States of America High 28193887
2017 Crystal structure of prokaryotic TMEM175 (CmTMEM175) reveals a novel tetrameric architecture completely different from canonical K+ channels. All six transmembrane helices are tightly packed within each subunit without domain swapping. TM1 acts as the pore-lining inner helix creating an hourglass-shaped ion permeation pathway. Three layers of hydrophobic residues on TM1 form the selectivity filter; mutagenesis showed the first conserved isoleucine layer is primarily responsible for channel selectivity. X-ray crystallography of prokaryotic TMEM175; site-directed mutagenesis; electrophysiology Nature High 28723891
2019 The TMEM175 p.M393T variant (rs34311866) reduces lysosomal pH regulation in response to starvation, reduces lysosomal localization, and increases accumulation of phosphorylated α-synuclein with effects intermediate between WT and knockout. Overexpression of WT TMEM175 reduced p-α-syn, while overexpression of p.M393T did not change α-synuclein phosphorylation. shRNA knockdown of only TMEM175 (not neighboring genes) consistently influenced accumulation of phosphorylated α-synuclein. shRNA knockdown screen; variant overexpression; lysosomal pH assay; autophagy substrate clearance assay; phospho-α-syn immunostaining; lysosomal localization imaging Human molecular genetics High 31261387
2019 The TMEM175 p.M393T variant creates a polar side-chain in the hydrophobic core of the transmembrane domain predicted to destabilize assembly, maturation, or trafficking, and is associated with reduced glucocerebrosidase (GCase) activity. Lysosomal localization of both p.M393T and p.Q65P variants was not affected. Molecular dynamics simulations suggested p.Q65P may increase stability and ion conductance. Homology modeling; normal mode analysis; molecular dynamics simulations; lysosomal localization experiments; GCase activity assay in patient cohort Annals of neurology Medium 31658403
2020 Cryo-EM structures of human TMEM175 in open and closed conformations (up to 2.6 Å resolution) reveal a homodimeric architecture with a central ion-conduction pore. Conserved isoleucine residues in the center of the pore serve as the gate in the closed conformation and establish a constriction essential for K+ selectivity in the open conformation. Cryo-EM structure determination; mutagenesis; electrophysiology eLife High 32228865
2020 X-ray structure of a closed bacterial TMEM175 channel in complex with a nanobody fusion-protein revealed bound K+ ions and a highly conserved layer of threonine residues in the pore that confers basal K+ selectivity. An additional layer comprising two serines in human TMEM175 increases selectivity further and renders the channel sensitive to 4-aminopyridine and Zn2+. Large hydrophobic side chains occlude the pore forming a physical gate; channel opening by iris-like motions simultaneously relocates the gate and exposes the selectivity filter. X-ray crystallography; electrophysiology; mutagenesis eLife High 32267231
2020 TMEM175 deficiency in neurons inhibits lysosomal hydrolytic function by affecting lysosomal pH, impairs autophagosome-lysosome fusion, and leads to impaired mitochondrial accumulation (failure to clear damaged mitochondria). Exogenous upregulation of TMEM175 reversed OGD/R-induced lysosomal dysfunction in cultured neurons. Lysosomal pH assay (LysoSensor, acridine orange); cathepsin B and D activity assays; TMEM175 overexpression/knockdown in cultured neurons and in vivo MCAO/R model Molecular brain Medium 32799888
2022 TMEM175 acts as a proton-activated, proton-selective channel (LyPAP) on the lysosomal membrane that mediates the lysosomal H+ leak. Acidification beyond the normal range (below pH 4.5–5.0) potently activated the channel to prevent further lysosomal acidification. 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 analysis showed the H+ conductance is essential for normal lysosome function. Lysosomal patch-clamp electrophysiology; ion substitution experiments; mutagenesis; lysosomal pH measurement; proteolytic activity assays; in vivo α-synuclein aggregation model Cell High 35750034
2022 Human TMEM175 exhibits pH-dependent structural changes: it constitutively conducts K+ at pH 7.4 but shows reduced K+ permeation at acidic pH, while proton current increases with decreasing pH. Molecular dynamics simulation, structure-based mutagenesis, and electrophysiology indicate K+ ions and protons share the same permeation pathway. The M393T PD-risk variant shows reduced function in both K+ and proton permeation. Cryo-EM structural analysis; whole-endolysosome patch-clamp electrophysiology; molecular dynamics simulations; site-directed mutagenesis Science advances High 35333573
2022 Bcl-2 binds to and inhibits TMEM175 channel activity. Bcl-2 inhibitors activate TMEM175 in a caspase-independent manner. Increased TMEM175 function inhibits mitophagy, disrupts mitochondrial homeostasis, and increases reactive oxygen species (ROS) production. ROS further activates TMEM175, forming a positive feedback loop to augment apoptosis. In an MPTP mouse model of PD, TMEM175 knockout mitigated motor impairment and dopaminergic neuron loss. Co-immunoprecipitation (Bcl-2/TMEM175 binding); lysosomal patch-clamp; Bcl-2 inhibitor treatment; ROS measurement; mitophagy assay; TMEM175 KO mouse MPTP model with behavioral and histological readouts EMBO reports High 35913019
2022 Higher-resolution cryo-EM structures of open and closed human TMEM175 and molecular dynamics simulations demonstrate that the open-state pore is permeable to both K+ and (to a lesser degree) Na+. Both cations must dehydrate significantly to penetrate the narrow hydrophobic constriction, but ion flow is assisted by a favorable electrostatic field. The balance of ion dehydration energetics explains K+ selectivity over Na+ despite absence of a canonical selectivity filter. Mutagenesis experiments confirmed exquisite sensitivity of channel selectivity to perturbations that mitigate the constriction. Cryo-EM structure determination (higher resolution than prior); molecular dynamics simulations; mutagenesis; electrophysiology eLife High 35608336
2022 Cryo-EM structure of TMEM175 bound to 4-aminopyridine (4-AP) shows that 4-AP binds near the center of the ion conduction pathway in the open state. MD simulations show the binding site is near the middle of the transmembrane potential gradient, explaining voltage-dependent dissociation. Bound 4-AP rapidly switches between three predominant binding poses stabilized by the twofold symmetry of the channel, and prevents both ion permeation and water flow. Cryo-EM structure of inhibitor-bound TMEM175; molecular dynamics simulations Proceedings of the National Academy of Sciences of the United States of America High 36279431
2021 TMEM175 is regulated by protein kinase B (PKB/Akt) and dynamin-dependent endocytosis. Dynamin inhibitors (dynasore, dyngo-4a) substantially increased TMEM175 currents at the plasma membrane by preventing channel internalization. A constitutively active Akt mutant and the Akt activator SC79 increased TMEM175 current, while the allosteric Akt inhibitor MK2206 diminished it. TMEM175 is more permeable to cesium than potassium and is voltage-dependently blocked by 4-AP. Two-electrode voltage clamp in Xenopus oocytes; dominant-negative dynamin coexpression; immunocytochemistry for surface TMEM175; pharmacological Akt manipulation International journal of molecular sciences Medium 34638858
2023 TMEM175 mediates both lysosomal H+ influx (refilling) and H+ efflux (releasing) in an asymmetric manner. Using whole-endolysosome patch-clamp in enlarged lysosomes under physiological pH gradient, integrated lysosomal H+ flux signals were recorded. Loss-of-function F39V mutant and the antagonist 2-GBI abolished all lysosomal H+ fluxes. LAMP1 glycosylation modulates these H+ fluxes. Whole-endolysosome patch-clamp in vacuolin-1-enlarged lysosomes; TMEM175 loss-of-function mutant (F39V); pharmacological block (2-GBI); LAMP1 manipulation The FEBS journal Medium 37165739
2023 Solid-supported membrane-based electrophysiology (SSME) of TMEM175 revealed two distinct conducting states (two-slope I/c curve for K+). H+ flux measurements yielded a permeability ratio PH/PK of ~48,500. Cytosolic pH decrease inhibited both K+ and H+ conductivity of TMEM175, while lysosomal-side pH changes did not have major effects. Tool compounds (4-AP, Zn2+ as inhibitors; DCPIB, arachidonic acid, SC-79 as enhancers) were validated across multiple assay formats. Solid-supported membrane-based electrophysiology (SSME); automated whole-cell patch-clamp (APC); lysosomal patch-clamp (LPC); pharmacological profiling International journal of molecular sciences Medium 37628970
2024 Cryo-EM structures of human TMEM175 bound to selective inhibitors 2-PPA and AP-6 reveal that they act as pore blockers, binding at distinct sites in the pore and occluding the ion permeation pathway. Acute inhibition by these inhibitors increases lysosomal macromolecule catabolism, accelerating macropinocytosis and other digestive processes. Cryo-EM structure of inhibitor-bound TMEM175; lysosomal catabolism assays; macropinocytosis assay Journal of the American Chemical Society High 39116214
2025 Rigorous re-examination found that in the lysosome, TMEM175 predominantly conducts K+ and is not a H+-selective channel. The native lysosomal H+ leak is ~0.02 fA, which is remarkably small and argues strongly against major H+ channel contributions. The predominant effect of TMEM175 deficiency is lysosomal alkalinization in challenged cells (not over-acidification), which is consistent with K+ conductance through TMEM175. Lysosomes can be hyper-acidified by manipulations in the presence or absence of TMEM175. Lysosomal patch-clamp electrophysiology; lysosomal pH measurement; genetic manipulation of TMEM175; ion substitution experiments The Journal of cell biology High 41134537
2025 Cryo-EM structures of human TMEM175 in complex with three agonists (DCY1020, DCY1040, TUG-891) captured an open state of the channel. DCY1020/1040 binds at the interface between two subunits, inducing an open conformation further augmented by synergistic agonist TUG-891. Surface plasmon resonance, systematic mutagenesis, whole-endolysosome patch-clamp, and MD simulations validated the binding sites. These agonists facilitate removal of pathological α-synuclein and restore function of PD-related TMEM175 variants in neurons. Cryo-EM structure; surface plasmon resonance; mutagenesis; whole-endolysosome patch-clamp; molecular dynamics simulations; α-synuclein clearance assay in neurons Neuron High 40865534
2025 Luminal-side H57 residue acts as a proton sensor critical for proton-selective gating of TMEM175. A pH drop from 7.4 to 4.7 on the luminal side triggers increased inward and outward currents with a transient shift in reversal potential toward H+ equilibrium voltage. H57 forms intra- and inter-subunit salt bridges with D279 and E282, stabilizing the open state. The H57Y mutant shows reduced H+ and K+ conductance and reduced H+/K+ selectivity, confirmed by both whole-cell and lysosomal electrophysiology. Whole-cell patch-clamp (plasma membrane redistributed TMEM175); lysosomal patch-clamp; molecular dynamics simulations; site-directed mutagenesis (H57Y); reversal potential measurements Proceedings of the National Academy of Sciences of the United States of America High 41533442
2025 TMEM175 conditional knockout in macrophages promotes anti-tumor immunity through elevated M1-like polarization, reduced M2-like polarization, and facilitated recruitment/activation of T cells and NK cells. The anti-tumor effect is abrogated by caspase-1 inhibitor VX-765, anti-IL-1β, and anti-IL-18. Tmem175-/- BMDMs show enhanced tumor antigen cross-presentation strengthened by IL-1β and IL-18. NLRP3 inflammasome is robustly activated in Tmem175-/- BMDMs via lysosomal permeabilization and cathepsin B leakage. Conditional macrophage-specific TMEM175 KO mouse; tumor growth/metastasis models; BMDM in vitro assays; caspase-1 inhibitor; neutralizing antibodies; cross-presentation assay; NLRP3 activation assay; cathepsin B leakage measurement Nature communications High 41690940
2024 TMEM175 deficiency in bone marrow-derived mesenchymal stem cells (BMSCs) suppresses osteoblast differentiation as evidenced by decreased matrix mineralization and lower expression of osteoblast marker genes. TMEM175 deficiency leads to lysosomal dysfunction and partially impairs autophagic clearance during osteoblast differentiation. The TMEM175 inhibitor 4-AP decreased osteoblast differentiation of BMSCs. TMEM175 knockdown in BMSCs; osteoblast differentiation assay (matrix mineralization, marker gene expression); lysosomal pH and function assays; autophagic flux measurement; 4-AP pharmacological inhibition Molecules and cells Medium 39426687
2026 TMEM175 activity in macrophages maintains lysosomal pH and prevents cholesterol accumulation. In BK channel-deficient (BK-/-) macrophages, TMEM175 is upregulated as a compensatory mechanism to maintain lysosomal function. Inhibition of TMEM175 activity in both BK-/- and WT macrophages increased lysosomal pH and reduced silica-induced cell death and IL-1β release, indicating TMEM175 regulates silica-induced inflammatory responses through lysosomal pH control. BK-/- mouse BMDM; TMEM175 inhibitor treatment; lysosomal pH assay; cholesterol accumulation assay; IL-1β measurement; cell death assay Inhalation toxicology Medium 40402504
2024 DABMA activates the endosomal TMEM175 channel with an EC50 of 17.9 μM as measured by organelle patch-clamp. Depletion of TMEM175 significantly decreases the antitoxin activity of DABMA and affects its action on acidic/Rab7-positive endosomes and endolysosomal trafficking, demonstrating that TMEM175 is necessary for DABMA's anti-pathogen activity. Organelle patch-clamp electrophysiology (EC50 determination); TMEM175 protein depletion; endosomal pH and Rab7 imaging; endolysosomal trafficking assays The FEBS journal Medium 39097908
2026 TMEM175 overexpression in cardiomyocytes confers cardioprotection after myocardial infarction by restoring lysosomal function (biogenesis, normalized pH, enzyme activities, and autophagic flux). Mechanistically, TMEM175 reduction caused by MI increases mTORC1 phosphorylation on lysosomal membranes and suppresses nuclear translocation of transcription factor EB (TFEB), impairing TFEB's transcriptional regulation of lysosome-associated genes. TMEM175 restoration reverses this cascade. Gain and loss of function in vivo MI model and in vitro hypoxia model; lysosomal pH/enzyme activity/biogenesis assays; mTORC1 phosphorylation measurement; TFEB nuclear translocation imaging; autophagic flux assay Acta pharmacologica Sinica Medium 41741766
2025 Mutagenesis identified T119 and H449 as structural determinants of TMEM175 activation gating. T119A and H449A mutations decreased apparent potencies of multiple TMEM175 activators (DCPIB, zafirlukast, montelukast). The T119A mutation produced a constitutively open channel phenotype. CysLT1 receptor antagonists (zafirlukast, montelukast, pranlukast) directly activate TMEM175 independently of CysLT1R, and DCPIB/zafirlukast activate TMEM175 independently of AKT, while montelukast activation is partially AKT-dependent. High-throughput screening; fluorescence assays; automated patch-clamp; mutagenesis (T119A, H449A); AKT inhibitor (MK2206) treatment; computational modeling American journal of physiology. Cell physiology Medium 41670588
2023 Functional analysis of novel TMEM175 mutations identified in PD patients (including p.R35C, p.R183X, p.A270T, p.P308L, p.S348L, p.L405V, p.R414W, p.P427fs, p.R481W) revealed loss of K+ conductance by patch-clamp and reduced channel affinity for Akt by co-immunoprecipitation. Patient-derived fibroblasts showed impaired autophagic/lysosomal proteolytic flux and increased unfolded protein response markers. Patch-clamp electrophysiology; co-immunoprecipitation (TMEM175-Akt); autophagic flux assay; UPR marker measurement in patient-derived fibroblasts Molecular neurobiology Medium 36609826

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation. Proceedings of the National Academy of Sciences of the United States of America 207 28193887
2015 TMEM175 Is an Organelle K(+) Channel Regulating Lysosomal Function. Cell 193 26317472
2022 Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes. Cell 191 35750034
2019 Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies. Annals of neurology 87 31658403
2019 Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease. Human molecular genetics 74 31261387
2017 The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture. Nature 60 28723891
2022 pH regulates potassium conductance and drives a constitutive proton current in human TMEM175. Science advances 44 35333573
2020 Structural basis for ion selectivity in TMEM175 K+ channels. eLife 43 32267231
2022 Lysosomal K+ channel TMEM175 promotes apoptosis and aggravates symptoms of Parkinson's disease. EMBO reports 38 35913019
2020 Gating and selectivity mechanisms for the lysosomal K+ channel TMEM175. eLife 34 32228865
2020 TMEM175 mediates Lysosomal function and participates in neuronal injury induced by cerebral ischemia-reperfusion. Molecular brain 32 32799888
2024 Resveratrol attenuates inflammation and fibrosis in rheumatoid arthritis-associated interstitial lung disease via the AKT/TMEM175 pathway. Journal of translational medicine 27 38745204
2023 TMEM175: A lysosomal ion channel associated with neurological diseases. Neurobiology of disease 22 37524211
2022 Differential ion dehydration energetics explains selectivity in the non-canonical lysosomal K+ channel TMEM175. eLife 22 35608336
2023 Common and Rare Variants in TMEM175 Gene Concur to the Pathogenesis of Parkinson's Disease in Italian Patients. Molecular neurobiology 18 36609826
2022 Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175. Proceedings of the National Academy of Sciences of the United States of America 18 36279431
2023 A Comparative Study on the Lysosomal Cation Channel TMEM175 Using Automated Whole-Cell Patch-Clamp, Lysosomal Patch-Clamp, and Solid Supported Membrane-Based Electrophysiology: Functional Characterization and High-Throughput Screening Assay Development. International journal of molecular sciences 11 37628970
2021 Translocation of TMEM175 Lysosomal Potassium Channel to the Plasma Membrane by Dynasore Compounds. International journal of molecular sciences 11 34638858
2015 Screening of polymorphisms located in the FGF20 and TMEM175 genes in North Chinese Parkinson's disease patients. Genetics and molecular research : GMR 10 26535683
2025 Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson's disease patients mutated in TMEM175. NPJ Parkinson's disease 8 39856101
2023 Characterization of the role of TMEM175 in an in vitro lysosomal H+ fluxes model. The FEBS journal 7 37165739
2023 TMEM175 downregulation participates in impairment of the autophagy related lysosomal dynamics following neonatal hypoxic-ischemic brain injury. Journal of cellular physiology 7 37566721
2025 Unraveling pH Regulation of TMEM175, an Endolysosomal Cation Channel With a Role in Parkinson's Disease. Journal of cellular physiology 6 39902728
2025 TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification. The Journal of cell biology 6 41134537
2024 Discovery of Selective Inhibitors for the Lysosomal Parkinson's Disease Channel TMEM175. Journal of the American Chemical Society 6 39116214
2024 TMEM175 plays a crucial role in osteoblast differentiation by regulating lysosomal function and autophagy. Molecules and cells 6 39426687
2025 Structural insights into the activation of TMEM175 by small molecule. Neuron 4 40865534
2024 Mechanism and therapeutic targets of the involvement of a novel lysosomal proton channel TMEM175 in Parkinson's disease. Ageing research reviews 4 38960046
2026 Proton-selective conductance and gating of the lysosomal cation channel TMEM175. Proceedings of the National Academy of Sciences of the United States of America 2 41533442
2025 Is the Parkinson's-associated protein TMEM175 a proton channel: Yay or nay? The Journal of cell biology 2 41295951
2025 Targeting TMEM175 in Lysosomal Physiology and Human Diseases. Current stem cell research & therapy 1 40776652
2024 Systemic knockout of Tmem175 results in aberrant differentiation but no effect on hematopoietic reconstitution. Stem cell research 1 38878670
2024 Endolysosomal channel TMEM175 mediates antitoxin activity of DABMA. The FEBS journal 1 39097908
2026 Activation of TMEM175 lysosomal ion channels by CysLT1 receptor antagonists. American journal of physiology. Cell physiology 0 41670588
2026 Deficiency of lysosomal TMEM175 in myeloid macrophages exerts anti-tumor immunity via inflammasome and cross-presentation pathway. Nature communications 0 41690940
2026 TMEM175 rescues post-infarct cardiac dysfunction via mTORC1-lysosomal axis modulation. Acta pharmacologica Sinica 0 41741766
2025 What We Know About TMEM175 in Parkinson's Disease. CNS neuroscience & therapeutics 0 39834146
2025 TMEM175 activity in BK-deficient macrophages maintains lysosomal function and mediates silica-induced inflammatory response in macrophages. Inhalation toxicology 0 40402504

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