TMEM175 review notes

Why this gene was selected

Flagged in projects/FUNCTION_KNOWLEDGE_GAPS/contested-functions-2025-2026.md as the sharpest
contested-function case found in the 2025-2026 literature: GOA carries proton channel activity
and potassium ion leak channel activity for the same protein, each with IDA support, and two
2026 papers reach opposite conclusions about which is the physiological function.

The K+ channel assignment (consensus)

TMEM175 was identified as the endolysosomal K+ leak conductance:
PMID:26317472 and PMID:26317472.

Independently confirmed with structure-function analysis of selectivity in the absence of a
canonical TVGYG filter: PMID:32228865.

Structural work on the prokaryotic ortholog established the selectivity series:
PMID:28723891.

The H+ channel assignment (contested)

Three groups reported proton conduction:
PMID:35750034, PMID:35333573, and PMID:37390818.

This is directly challenged in 2026:
PMID:41134537 with the key phenotypic argument
PMID:41134537.

The opposing 2026 position maintains proton selectivity at acidic luminal pH:
PMID:41533442.

A Journal of Cell Biology commentary summarises the state of play:
PMID:41295951

Curation position taken

• GO:0022841 potassium ion leak channel activity → core. Supported by independent labs across
  a decade, and not contested by either 2026 paper (both agree K+ conductance dominates at neutral pH).
• GO:0015252 proton channel activity and the associated BP terms (GO:0035752, GO:1902600) →
  KEEP_AS_NON_CORE, with the dispute recorded in each reason. Not removed: these are
  experimental annotations whose underlying recordings are real, and a channel can be genuinely
  H+-permeable without that being its physiological role. Per project rules, an IDA is not
  overruled from an abstract.
• GO:0005267 potassium channel activity → MODIFY to GO:0022841; correct in kind but
  under-specific, since the channel is constitutively open rather than gated.
• GO:0050544 arachidonate binding → non-core modulatory input.
• Bare protein binding → over-annotated.

Open question for experts

Is the disagreement reconcilable as a difference in recording configuration (luminal pH, excised
patch vs whole-lysosome) rather than a contradiction? Both 2026 papers agree K+ dominates at
neutral pH; they disagree about behaviour at acidic luminal pH and about the magnitude of the
native lysosomal H+ leak.