TMEM175

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005764 lysosome	IBA GO_REF:0000033	ACCEPT	Summary: TMEM175 resides in this compartment; the assertion is correct. Reason: Correct, though the lysosomal membrane (GO:0005765) annotation carried by this gene is more informative about where the channel sits.
GO:0005768 endosome	IBA GO_REF:0000033	ACCEPT	Summary: TMEM175 resides in this compartment; the assertion is correct. Reason: Correct, though the endosome membrane (GO:0010008) annotation carried by this gene is more informative about where the channel sits.
GO:0022841 potassium ion leak channel activity	IBA GO_REF:0000033	ACCEPT	Summary: The phylogenetic assertion matches the experimentally established function: TMEM175 is a constitutively active, voltage-independent K+ leak channel of endolysosomal membranes. Reason: Core molecular function, supported by independent experimental work in multiple labs. Supporting Evidence: PMID:26317472 Here, we directly recorded organelle K(+) conductance and discovered a major K(+)-selective channel KEL on endosomes and lysosomes. KEL is formed by TMEM175, a protein with unknown function. PMID:32228865 Transmembrane protein 175 (TMEM175) was recently identified as a constitutively-active potassium (K+) selective channel expressed in lysosomal membranes responsible for establishing a membrane potential across the lysosomal membrane
GO:0005267 potassium channel activity	IEA GO_REF:0000002	MODIFY	Summary: Correct in kind but under-specific: TMEM175 is not a gated potassium channel but a constitutively open leak conductance. Reason: A more specific term is available and better represents the measured biophysics. Proposed replacements: potassium ion leak channel activity
GO:0005765 lysosomal membrane	IEA GO_REF:0000044	ACCEPT	Summary: TMEM175 is a multi-pass protein of the lysosomal membrane. Reason: Correct and specific primary location.
GO:0010008 endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: TMEM175 also resides in late endosomal membranes. Reason: Correct secondary location.
GO:0015252 proton channel activity	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Electronic assignment of proton channel activity from the InterPro signature. Reason: The proton-conductance assignment is contested. Three independent groups reported H+ conduction by TMEM175 (PMID:35333573, PMID:35750034, PMID:37390818), but Riederer et al. 2026 report that in lysosomes TMEM175 predominantly conducts K+, that the native lysosomal H+ leak is vanishingly small, and that TMEM175 knockout alkalinizes rather than acidifies lysosomes - the opposite of the proton-leak prediction (PMID:41134537). A same-year PNAS study maintains proton-selective conductance at acidic luminal pH (PMID:41533442), and a Journal of Cell Biology commentary frames the question as open (PMID:41295951). Retained, because the underlying recordings are real and a channel can be genuinely H+-permeable without that being its physiological role, but demoted from core pending resolution.
GO:0022841 potassium ion leak channel activity	IEA GO_REF:0000107	ACCEPT	Summary: Orthology-based transfer agreeing with the human experimental data. Reason: Consistent with the core K+ leak function.
GO:0070050 neuron cellular homeostasis	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: A distal organismal phenotype rather than a process TMEM175 protein carries out. Reason: Downstream consequence of lysosomal ion homeostasis in neurons; not a direct role.
GO:0071805 potassium ion transmembrane transport	IEA GO_REF:0000107	ACCEPT	Summary: K+ movement across the endolysosomal membrane is the direct consequence of the channel activity. Reason: Core biological process.
GO:0090385 phagosome-lysosome fusion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Loss of TMEM175 perturbs autophagosome/lysosome and phagosome/lysosome fusion. Reason: Real but downstream of the ion-transport function.
GO:0005765 lysosomal membrane	EXP PMID:26317472 TMEM175 Is an Organelle K(+) Channel Regulating Lysosomal Fu...	ACCEPT	Summary: Experimental localisation to the lysosomal membrane. Reason: Well-supported core location.
GO:0005765 lysosomal membrane	EXP PMID:31261387 Functionalization of the TMEM175 p.M393T variant as a risk f...	ACCEPT	Summary: Experimental localisation to the lysosomal membrane. Reason: Well-supported core location.
GO:0005765 lysosomal membrane	EXP PMID:31658403 Genetic, Structural, and Functional Evidence Link TMEM175 to...	ACCEPT	Summary: Experimental localisation to the lysosomal membrane. Reason: Well-supported core location.
GO:0010008 endosome membrane	EXP PMID:26317472 TMEM175 Is an Organelle K(+) Channel Regulating Lysosomal Fu...	ACCEPT	Summary: Experimental localisation to endosome membranes. Reason: Well-supported secondary location. Supporting Evidence: PMID:26317472 Here, we directly recorded organelle K(+) conductance and discovered a major K(+)-selective channel KEL on endosomes and lysosomes. KEL is formed by TMEM175, a protein with unknown function.
GO:0005515 protein binding	IPI PMID:37390818 Lysosomal LAMP proteins regulate lysosomal pH by direct inhi...	REMOVE	Summary: Bare protein binding carries no functional information. Reason: No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Here the partner interaction is captured by the LAMP-mediated regulation described in the source. Removal does not imply the reported interaction is false.
GO:0015252 proton channel activity	IDA PMID:37390818 Lysosomal LAMP proteins regulate lysosomal pH by direct inhi...	KEEP AS NON CORE	Summary: Direct measurement of TMEM175-mediated H+ current, reported together with its inhibition by LAMP proteins. Reason: The proton-conductance assignment is contested. Three independent groups reported H+ conduction by TMEM175 (PMID:35333573, PMID:35750034, PMID:37390818), but Riederer et al. 2026 report that in lysosomes TMEM175 predominantly conducts K+, that the native lysosomal H+ leak is vanishingly small, and that TMEM175 knockout alkalinizes rather than acidifies lysosomes - the opposite of the proton-leak prediction (PMID:41134537). A same-year PNAS study maintains proton-selective conductance at acidic luminal pH (PMID:41533442), and a Journal of Cell Biology commentary frames the question as open (PMID:41295951). Retained, because the underlying recordings are real and a channel can be genuinely H+-permeable without that being its physiological role, but demoted from core pending resolution. Supporting Evidence: PMID:37390818 Upon changing the bath pH to acidic conditions, TMEM175 becomes a proton-activated proton channel conducting a higher inward proton current at lower pH (Figure 2C).
GO:0035752 lysosomal lumen pH elevation	IDA PMID:37390818 Lysosomal LAMP proteins regulate lysosomal pH by direct inhi...	KEEP AS NON CORE	Summary: TMEM175-mediated H+ efflux proposed to raise lysosomal luminal pH. Reason: The proton-conductance assignment is contested. Three independent groups reported H+ conduction by TMEM175 (PMID:35333573, PMID:35750034, PMID:37390818), but Riederer et al. 2026 report that in lysosomes TMEM175 predominantly conducts K+, that the native lysosomal H+ leak is vanishingly small, and that TMEM175 knockout alkalinizes rather than acidifies lysosomes - the opposite of the proton-leak prediction (PMID:41134537). A same-year PNAS study maintains proton-selective conductance at acidic luminal pH (PMID:41533442), and a Journal of Cell Biology commentary frames the question as open (PMID:41295951). Retained, because the underlying recordings are real and a channel can be genuinely H+-permeable without that being its physiological role, but demoted from core pending resolution.
GO:1902600 proton transmembrane transport	IDA PMID:37390818 Lysosomal LAMP proteins regulate lysosomal pH by direct inhi...	KEEP AS NON CORE	Summary: Proton movement across the lysosomal membrane attributed to TMEM175. Reason: The proton-conductance assignment is contested. Three independent groups reported H+ conduction by TMEM175 (PMID:35333573, PMID:35750034, PMID:37390818), but Riederer et al. 2026 report that in lysosomes TMEM175 predominantly conducts K+, that the native lysosomal H+ leak is vanishingly small, and that TMEM175 knockout alkalinizes rather than acidifies lysosomes - the opposite of the proton-leak prediction (PMID:41134537). A same-year PNAS study maintains proton-selective conductance at acidic luminal pH (PMID:41533442), and a Journal of Cell Biology commentary frames the question as open (PMID:41295951). Retained, because the underlying recordings are real and a channel can be genuinely H+-permeable without that being its physiological role, but demoted from core pending resolution.
GO:0005765 lysosomal membrane	IDA PMID:35750034 Parkinson's disease-risk protein TMEM175 is a proton-activat...	ACCEPT	Summary: TMEM175 is active in the lysosomal membrane. Reason: Correct and specific.
GO:0015252 proton channel activity	IDA PMID:35333573 pH regulates potassium conductance and drives a constitutive...	KEEP AS NON CORE	Summary: Constitutive proton current recorded from human TMEM175 at acidic luminal pH. Reason: The proton-conductance assignment is contested. Three independent groups reported H+ conduction by TMEM175 (PMID:35333573, PMID:35750034, PMID:37390818), but Riederer et al. 2026 report that in lysosomes TMEM175 predominantly conducts K+, that the native lysosomal H+ leak is vanishingly small, and that TMEM175 knockout alkalinizes rather than acidifies lysosomes - the opposite of the proton-leak prediction (PMID:41134537). A same-year PNAS study maintains proton-selective conductance at acidic luminal pH (PMID:41533442), and a Journal of Cell Biology commentary frames the question as open (PMID:41295951). Retained, because the underlying recordings are real and a channel can be genuinely H+-permeable without that being its physiological role, but demoted from core pending resolution. Supporting Evidence: PMID:35333573 pH regulates potassium conductance and drives a constitutive proton current in human TMEM175.
GO:0015252 proton channel activity	IDA PMID:35750034 Parkinson's disease-risk protein TMEM175 is a proton-activat...	KEEP AS NON CORE	Summary: TMEM175 characterised as a proton-activated proton channel. Reason: The proton-conductance assignment is contested. Three independent groups reported H+ conduction by TMEM175 (PMID:35333573, PMID:35750034, PMID:37390818), but Riederer et al. 2026 report that in lysosomes TMEM175 predominantly conducts K+, that the native lysosomal H+ leak is vanishingly small, and that TMEM175 knockout alkalinizes rather than acidifies lysosomes - the opposite of the proton-leak prediction (PMID:41134537). A same-year PNAS study maintains proton-selective conductance at acidic luminal pH (PMID:41533442), and a Journal of Cell Biology commentary frames the question as open (PMID:41295951). Retained, because the underlying recordings are real and a channel can be genuinely H+-permeable without that being its physiological role, but demoted from core pending resolution. Supporting Evidence: PMID:35750034 Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes.
GO:0035752 lysosomal lumen pH elevation	IDA PMID:35333573 pH regulates potassium conductance and drives a constitutive...	KEEP AS NON CORE	Summary: Lysosomal pH elevation attributed to TMEM175 H+ efflux. Reason: The proton-conductance assignment is contested. Three independent groups reported H+ conduction by TMEM175 (PMID:35333573, PMID:35750034, PMID:37390818), but Riederer et al. 2026 report that in lysosomes TMEM175 predominantly conducts K+, that the native lysosomal H+ leak is vanishingly small, and that TMEM175 knockout alkalinizes rather than acidifies lysosomes - the opposite of the proton-leak prediction (PMID:41134537). A same-year PNAS study maintains proton-selective conductance at acidic luminal pH (PMID:41533442), and a Journal of Cell Biology commentary frames the question as open (PMID:41295951). Retained, because the underlying recordings are real and a channel can be genuinely H+-permeable without that being its physiological role, but demoted from core pending resolution.
GO:0035752 lysosomal lumen pH elevation	IDA PMID:35750034 Parkinson's disease-risk protein TMEM175 is a proton-activat...	KEEP AS NON CORE	Summary: Lysosomal pH elevation attributed to TMEM175 H+ efflux. Reason: The proton-conductance assignment is contested. Three independent groups reported H+ conduction by TMEM175 (PMID:35333573, PMID:35750034, PMID:37390818), but Riederer et al. 2026 report that in lysosomes TMEM175 predominantly conducts K+, that the native lysosomal H+ leak is vanishingly small, and that TMEM175 knockout alkalinizes rather than acidifies lysosomes - the opposite of the proton-leak prediction (PMID:41134537). A same-year PNAS study maintains proton-selective conductance at acidic luminal pH (PMID:41533442), and a Journal of Cell Biology commentary frames the question as open (PMID:41295951). Retained, because the underlying recordings are real and a channel can be genuinely H+-permeable without that being its physiological role, but demoted from core pending resolution.
GO:0050544 arachidonate binding	IDA PMID:35750034 Parkinson's disease-risk protein TMEM175 is a proton-activat...	KEEP AS NON CORE	Summary: Arachidonic acid activates TMEM175 currents. Reason: A genuine direct binding/activation observation, but a modulatory input rather than the core function. Supporting Evidence: PMID:35750034 Arachidonic acid (ArA), a polyunsaturated fatty acid involved in numerous cellular signaling events, reportedly increases permeability to K+ and H+ in isolated lysosomes
GO:1902600 proton transmembrane transport	IDA PMID:35333573 pH regulates potassium conductance and drives a constitutive...	KEEP AS NON CORE	Summary: Proton transport attributed to TMEM175. Reason: The proton-conductance assignment is contested. Three independent groups reported H+ conduction by TMEM175 (PMID:35333573, PMID:35750034, PMID:37390818), but Riederer et al. 2026 report that in lysosomes TMEM175 predominantly conducts K+, that the native lysosomal H+ leak is vanishingly small, and that TMEM175 knockout alkalinizes rather than acidifies lysosomes - the opposite of the proton-leak prediction (PMID:41134537). A same-year PNAS study maintains proton-selective conductance at acidic luminal pH (PMID:41533442), and a Journal of Cell Biology commentary frames the question as open (PMID:41295951). Retained, because the underlying recordings are real and a channel can be genuinely H+-permeable without that being its physiological role, but demoted from core pending resolution.
GO:1902600 proton transmembrane transport	IDA PMID:35750034 Parkinson's disease-risk protein TMEM175 is a proton-activat...	KEEP AS NON CORE	Summary: Proton transport attributed to TMEM175. Reason: The proton-conductance assignment is contested. Three independent groups reported H+ conduction by TMEM175 (PMID:35333573, PMID:35750034, PMID:37390818), but Riederer et al. 2026 report that in lysosomes TMEM175 predominantly conducts K+, that the native lysosomal H+ leak is vanishingly small, and that TMEM175 knockout alkalinizes rather than acidifies lysosomes - the opposite of the proton-leak prediction (PMID:41134537). A same-year PNAS study maintains proton-selective conductance at acidic luminal pH (PMID:41533442), and a Journal of Cell Biology commentary frames the question as open (PMID:41295951). Retained, because the underlying recordings are real and a channel can be genuinely H+-permeable without that being its physiological role, but demoted from core pending resolution.
GO:0005515 protein binding	IPI PMID:33505021 A growth-factor-activated lysosomal K(+) channel regulates P...	REMOVE	Summary: Bare protein binding from a large-scale interaction study. Reason: Uninformative as a molecular function. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false.
GO:0005764 lysosome	IDA PMID:31261387 Functionalization of the TMEM175 p.M393T variant as a risk f...	ACCEPT	Summary: TMEM175 resides in this compartment; the assertion is correct. Reason: Correct, though the lysosomal membrane (GO:0005765) annotation carried by this gene is more informative about where the channel sits.
GO:0005764 lysosome	IDA PMID:31658403 Genetic, Structural, and Functional Evidence Link TMEM175 to...	ACCEPT	Summary: TMEM175 resides in this compartment; the assertion is correct. Reason: Correct, though the lysosomal membrane (GO:0005765) annotation carried by this gene is more informative about where the channel sits.
GO:0005765 lysosomal membrane	IDA PMID:32228865 Gating and selectivity mechanisms for the lysosomal K(+) cha...	ACCEPT	Summary: Experimental localisation to the lysosomal membrane. Reason: Well-supported core location.
GO:0010008 endosome membrane	IDA PMID:32228865 Gating and selectivity mechanisms for the lysosomal K(+) cha...	ACCEPT	Summary: Experimental localisation to endosome membranes. Reason: Well-supported secondary location.
GO:0022841 potassium ion leak channel activity	IDA PMID:32228865 Gating and selectivity mechanisms for the lysosomal K(+) cha...	ACCEPT	Summary: Direct recording and structure-function analysis of TMEM175 as a K+-selective leak channel, including the basis of its selectivity in the absence of a canonical TVGYG filter. Reason: Core molecular function. Supporting Evidence: PMID:32228865 Transmembrane protein 175 (TMEM175) was recently identified as a constitutively-active potassium (K+) selective channel expressed in lysosomal membranes responsible for establishing a membrane potential across the lysosomal membrane
GO:0070050 neuron cellular homeostasis	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Orthology-projected organismal phenotype. Reason: Distal to the molecular function.
GO:0071805 potassium ion transmembrane transport	IDA PMID:32228865 Gating and selectivity mechanisms for the lysosomal K(+) cha...	ACCEPT	Summary: K+ flux across the endolysosomal membrane. Reason: Core biological process.
GO:0005267 potassium channel activity	IDA PMID:28723891 The lysosomal potassium channel TMEM175 adopts a novel tetra...	MODIFY	Summary: Structural and flux work establishing K+ selectivity; the general potassium channel term understates the constitutive leak behaviour. Reason: A more specific term is available. Proposed replacements: potassium ion leak channel activity Supporting Evidence: PMID:28723891 These results show that CmTMEM175 is selective for K+, Rb+ and Cs+ over Na+, consistent with the selectivity of the eukaryotic TMEM175.
GO:0071805 potassium ion transmembrane transport	IDA PMID:28723891 The lysosomal potassium channel TMEM175 adopts a novel tetra...	ACCEPT	Summary: K+ permeation demonstrated by flux assay. Reason: Core biological process.
GO:0005764 lysosome	IDA PMID:26317472 TMEM175 Is an Organelle K(+) Channel Regulating Lysosomal Fu...	ACCEPT	Summary: TMEM175 resides in this compartment; the assertion is correct. Reason: Correct, though the lysosomal membrane (GO:0005765) annotation carried by this gene is more informative about where the channel sits.
GO:0005768 endosome	IDA PMID:26317472 TMEM175 Is an Organelle K(+) Channel Regulating Lysosomal Fu...	ACCEPT	Summary: TMEM175 resides in this compartment; the assertion is correct. Reason: Correct, though the endosome membrane (GO:0010008) annotation carried by this gene is more informative about where the channel sits.
GO:0022841 potassium ion leak channel activity	IDA PMID:26317472 TMEM175 Is an Organelle K(+) Channel Regulating Lysosomal Fu...	ACCEPT	Summary: Founding identification of TMEM175 as the endolysosomal K+ leak conductance. Reason: Core molecular function. Supporting Evidence: PMID:26317472 Here, we directly recorded organelle K(+) conductance and discovered a major K(+)-selective channel KEL on endosomes and lysosomes. KEL is formed by TMEM175, a protein with unknown function. PMID:26317472 Lysosomes lacking TMEM175 exhibit no K(+) conductance, have a markedly depolarized
GO:0071805 potassium ion transmembrane transport	IDA PMID:26317472 TMEM175 Is an Organelle K(+) Channel Regulating Lysosomal Fu...	ACCEPT	Summary: K+ conductance across endolysosomal membranes. Reason: Core biological process.
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	ACCEPT	Summary: High-throughput proteomic localisation to the lysosomal membrane, consistent with all focused studies. Reason: Correct location.

Gene Description

Existing Annotations Review

Core Functions

References

📚 Additional Documentation

Notes

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