TMEM87A

TMEM87A is a Golgi-resident, GOLD-domain seven-transmembrane protein that links Golgi physiology to membrane trafficking, mechanotransduction, and tumor cell behavior (PMID:36373655, PMID:38992057). Its Golgi/TGN localization depends on retrograde tethering: TMEM87A overexpression partially rescues endosome-to-TGN retrograde transport in VPS54-null cells (PMID:26157166), and acute GARP-complex disruption mislocalizes and degrades the protein (PMID:40100055). A high-resolution cryo-EM structure positions TMEM87A within the GOLD-domain seven-transmembrane (GOST) family alongside the Wnt chaperone WLS, with a large membrane-facing cavity consistent with handling membrane-associated cargo (PMID:36373655). Functionally, TMEM87A operates as a voltage-dependent cation channel that maintains Golgi pH; its loss causes Golgi overacidification and fragmentation, altered glycosylation, and impaired spatial memory in knockout mice (PMID:38992057). The same channel activity is mechanically gated: TMEM87A reconstitutes mechanically activated currents in PIEZO1-deficient cells and is required for mechanotransduction in low-threshold mechanoreceptors, with its loss producing touch insensitivity in mice (PMID:32228863, PMID:38422143). Through its Golgi pH function, TMEM87A confers ferroptosis resistance by enabling FSP1-mediated coenzyme Q reduction, and its ablation suppresses tumor growth while enhancing antitumor T cell responses (PMID:42014864). TMEM87A further forms a mechanosensing complex with CHP1 that sustains WNT5A and Hedgehog/PTCH1 signaling, and its loss reduces melanoma motility and microgravity-dependent invasion linked to focal adhesion and YAP1 redistribution (PMID:40090965, PMID:42258092).

1. 2015 Medium

   Established TMEM87A as a Golgi protein functionally tied to retrograde membrane trafficking, the first clue to its cellular role.

   Evidence Genome-wide haploid screen plus overexpression rescue of transport in VPS54-knockout human cells

   PMID:26157166

   Open questions at the time

   • Did not define molecular mechanism by which TMEM87A supports transport
   • No direct interaction partners identified
   • Rescue was partial
2. 2020 High

   Showed TMEM87A is sufficient to generate mechanically activated currents independently of PIEZO1, reframing it as a candidate mechanotransduction channel and linking it to cell motility and adhesion.

   Evidence Heterologous expression in PIEZO1-deficient cells with patch-clamp, plus CRISPR knockout motility/adhesion assays in melanoma cells

   PMID:32228863

   Open questions at the time

   • Did not resolve whether TMEM87A is the pore-forming subunit
   • Gating mechanism unknown
   • Relationship between channel activity and Golgi trafficking role unresolved
3. 2020 Medium

   Demonstrated an oncogenic TMEM87A-RASGRF1 fusion can transform cells, an event involving the TMEM87A locus rather than its native channel function.

   Evidence RNA-seq fusion detection, NIH/3T3 transformation and CRISPR-edited PC9 cells with MAPK readout

   PMID:32312893

   Open questions at the time

   • Oncogenicity driven by RASGRF1 GEF activity, not native TMEM87A function
   • Contribution of the TMEM87A portion to fusion activity undefined
   • Single exceptional-responder context
4. 2022 High

   Provided the first structure, placing TMEM87A in the GOST family with WLS and supporting a membrane-cargo trafficking role, while structurally arguing against ion-channel/GPCR function.

   Evidence Cryo-EM in lipid nanodiscs with structural and functional comparison to WLS

   PMID:36373655

   Open questions at the time

   • Structural inference against channel function conflicts with electrophysiology
   • No cargo directly identified
   • Static structure does not capture gating or conduction
5. 2022 Low

   Linked TMEM87A TGN residence to Vti1a/b-dependent retrograde trafficking, reinforcing its dependence on retrograde transport machinery for steady-state localization.

   Evidence Immunofluorescence intensity quantification in Vti1a/b double-knockout neurons

   PMID:36460703

   Open questions at the time

   • Single localization measurement without mechanistic follow-up
   • No direct interaction with Vti1a/b shown
   • Functional consequence of mislocalization untested
6. 2024 High

   Resolved the channel controversy by demonstrating TMEM87A is a voltage-dependent cation channel that regulates Golgi pH, connecting its molecular activity to Golgi integrity, glycosylation and brain function in vivo.

   Evidence Patch-clamp with gluconate inhibition, multiple cryo-EM structures, and knockout mice with Golgi, glycosylation and memory phenotypes

   PMID:38992057

   Open questions at the time

   • Direct ion selectivity and conduction path not fully resolved
   • Mechanism coupling Golgi pH to glycosylation unclear
   • Reconciliation with 2022 structural channel-negative interpretation not fully addressed
7. 2024 High

   Established TMEM87A as necessary for touch sensation by genetically restoring mechanically activated currents in null neurons across mouse and human systems.

   Evidence Elkin1 knockout mice, neuronal rescue, behavioral touch assays, and siRNA knockdown in human induced sensory neurons with electrophysiology

   PMID:38422143

   Open questions at the time

   • Whether TMEM87A forms the pore versus an essential subunit unresolved
   • Force-transmission mechanism to the channel unknown
   • Link between Golgi channel role and surface mechanotransduction undefined
8. 2025 Medium

   Peer-reviewed confirmation that GARP-mediated retrograde tethering controls TMEM87A localization and stability, solidifying the trafficking dependence first seen in 2015.

   Evidence mAID degron VPS54 depletion with immunofluorescence and western blot

   PMID:40100055

   Open questions at the time

   • Direct GARP-TMEM87A contact not demonstrated
   • Degradation pathway upon mislocalization unidentified
   • Functional consequence on channel activity untested
9. 2025 Medium

   Connected TMEM87A to mechanically responsive tumor cell behavior, showing its requirement for microgravity-induced cytoskeletal, focal adhesion and YAP1 changes and spheroid invasion.

   Evidence ELKIN1 knockout cells under simulated microgravity with focal adhesion/YAP1 imaging and organotypic invasion assay

   PMID:40090965

   Open questions at the time

   • Mechanism linking TMEM87A to YAP1 redistribution unknown
   • Single-lab phenotypic study
   • Whether channel activity is required not tested
10. 2026 High

    Defined a Golgi pH-dependent role for TMEM87A in ferroptosis resistance and tumor progression, mechanistically coupling its pH-regulating activity to FSP1/coenzyme Q antioxidant defense.

    Evidence Knockout/depletion with Golgi pH, FSP1 activity and CoQ reduction assays plus multiple in vivo tumor models and immune profiling

    PMID:42014864

    Open questions at the time

    • How Golgi pH controls FSP1/CoQ chemistry mechanistically unclear
    • Direct versus indirect effect on FSP1 unresolved
    • Contribution of channel versus trafficking activity not separated
11. 2026 Medium

    Identified CHP1 as a direct physical partner forming a TMEM87A mechanosensing complex that drives WNT5A and Hedgehog signaling in tumor growth and metastasis.

    Evidence Co-IP, CETSA, MST, SPR binding assays plus CRISPR knockout in spheroids and orthotopic mouse models with pathway western blots

    PMID:42258092

    Open questions at the time

    • Mechanism by which the complex transduces signal to WNT/Hedgehog undefined
    • Single-lab characterization
    • Whether complex requires channel/mechanical activity untested

• It remains unresolved how TMEM87A's Golgi pH-regulating channel activity, its plasma-membrane mechanotransduction role, and its GOST-family cargo-trafficking function are mechanistically unified within one protein.
• No model reconciling Golgi-channel and surface mechanosensing roles
• Pore-forming versus accessory-subunit status not definitively established
• Native trafficking cargo not identified