Affinage

TMEM120A

Transmembrane protein 120A · UniProt Q9BXJ8

Length
343 aa
Mass
40.6 kDa
Annotated
2026-06-10
21 papers in source corpus 14 papers cited in narrative 14 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

TMEM120A is an ER and nuclear-envelope transmembrane protein that functions in lipid and coenzyme A (CoA) metabolism rather than as the mechanosensitive ion channel it was originally proposed to be (PMID:34374645, PMID:34374644, PMID:34409941). Convergent cryo-EM structures define a tightly packed homodimer in which each protomer forms a six-helix transmembrane α-barrel that binds a CoA molecule in a deep pocket through a conserved central tryptophan, with an architecture homologous to the fatty acid elongase ELOVL7 (PMID:34374645, PMID:34374644, PMID:34409941). As an ER-resident CoA-binding protein, TMEM120A interacts with the acyl-CoA synthetases ACSL1 and ACSL3 to promote long-chain acyl-CoA synthesis and fatty acid re-esterification, sustaining lipid cycling during lipolysis and protecting against ER stress (PMID:41423633). At the nuclear periphery it organizes the adipocyte genome and is required for adipocyte differentiation; its adipocyte-specific loss repositions metabolic genes, suppresses lipid metabolism programs, induces myogenic genes, and produces a lipodystrophy resembling human FPLD2 (PMID:26024229, PMID:35027552). Its nuclear pool further sustains nuclear CoA and acetyl-CoA levels to support histone acetylation, influencing chemotherapy sensitivity in colorectal cancer (PMID:37728615). Independently, TMEM120A acts as a negative modulator of mechanotransduction channels, decreasing PIEZO2 current amplitude and raising its activation threshold and inhibiting PKD2 channel activity through direct physical interaction (PMID:35819364, PMID:36420836). It also promotes innate antiviral signaling by binding STING and facilitating its ER-to-ERGIC translocation, enhancing TBK1/IRF3 phosphorylation and interferon-stimulated gene expression (PMID:35013224). Although early work reported intrinsic mechanosensitive channel activity, multiple independent structural and electrophysiological studies established that purified TMEM120A does not form a bona fide ion channel (PMID:34374644, PMID:34409941).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2015 Medium

    Established the first cellular role for TMEM120A by placing it at the nuclear envelope and showing it is required for fat-cell differentiation, framing it as a nuclear-periphery protein with a metabolic function.

    Evidence siRNA knockdown in 3T3-L1 cells with qPCR of differentiation markers, lipid staining/CARS microscopy, and subcellular localization

    PMID:26024229

    Open questions at the time
    • Molecular mechanism linking nuclear-envelope localization to differentiation gene expression not defined
    • No biochemical activity assigned
    • Single cell-line model
  2. 2020 Medium

    Proposed TMEM120A (TACAN) as an intrinsic mechanosensitive ion channel underlying nociceptor mechanotransduction, raising the central question of whether the protein conducts ions.

    Evidence Heterologous expression, purification and lipid reconstitution, nociceptor-specific inducible knockout with behavior and patch-clamp

    PMID:32084332

    Open questions at the time
    • Channel activity not structurally substantiated
    • Reconstitution conduction could reflect artifact
    • Contested by subsequent independent groups
  3. 2021 High

    Resolved the protein's true biochemical identity: independent cryo-EM structures showed a dimeric ELOVL-like fatty acid elongase fold with a bound CoA cofactor and no ion channel pore, directly refuting the channel model.

    Evidence Single-particle cryo-EM (CoA-bound and apo), native/MS CoA identification, mutagenesis of the CoA-binding tryptophan, and patch-clamp/reconstitution electrophysiology across three labs

    PMID:34374644 PMID:34374645 PMID:34409941

    Open questions at the time
    • Catalytic or transport function of the CoA pocket not directly demonstrated
    • Physiological consequence of apo-vs-CoA conformational switch unknown
  4. 2022 High

    Reframed TMEM120A as a modulator rather than effector of mechanotransduction, showing it specifically dampens PIEZO2 and inhibits PKD2 channel activity through physical interaction.

    Evidence Heterologous co-expression and reciprocal siRNA patch-clamp for PIEZO2; Co-IP, two-electrode/single-channel electrophysiology, fragment mapping, and zebrafish model for PKD2

    PMID:35819364 PMID:36420836

    Open questions at the time
    • Structural basis of PIEZO2 modulation not resolved
    • Whether CoA binding is required for channel modulation unknown
    • Endogenous tissue relevance of PKD2 inhibition incompletely defined
  5. 2022 High

    Identified an unexpected immune function, showing TMEM120A binds STING and drives its ER-to-ERGIC trafficking to potentiate antiviral interferon signaling.

    Evidence Genome-wide overexpression screen, Co-IP, subcellular localization assays, knockout MEFs, and TBK1/IRF3 phospho-readouts

    PMID:35013224

    Open questions at the time
    • Mechanism by which TMEM120A promotes STING translocation unclear
    • Link between CoA/lipid function and STING trafficking not established
  6. 2022 Medium

    Extended the negative-regulator role to a conserved reproductive context, showing the C. elegans ortholog genetically antagonizes the PIEZO ortholog pezo-1.

    Evidence Loss-of-function deletion, auxin-inducible degradation, live imaging, and double-mutant epistasis in C. elegans

    PMID:38051962

    Open questions at the time
    • Direct physical interaction with PIEZO not shown in worm
    • Molecular mechanism of antagonism unresolved
  7. 2022 High

    Established the in vivo physiological importance of the nuclear-periphery function, linking TMEM120A loss to genome misorganization and a lipodystrophy phenotype mirroring human FPLD2.

    Evidence Adipocyte-specific knockout mice with 3D genome organization analysis, RNA-seq, metabolic phenotyping, and FPLD2 patient cell comparison

    PMID:35027552

    Open questions at the time
    • Mechanism connecting CoA-binding biochemistry to spatial genome organization unknown
    • Whether genome repositioning is a direct or downstream effect unclear
  8. 2023 Medium

    Connected TMEM120A's CoA function to chromatin regulation, showing its nuclear pool sustains nuclear CoA/acetyl-CoA and histone acetylation to set chemotherapy sensitivity.

    Evidence CRISPR knockout, localization-variant overexpression, histone acid extraction/western blot, and pharmacological acetylation inhibition in colorectal cancer cells

    PMID:37728615

    Open questions at the time
    • Direct measurement of TMEM120A-dependent acetyl-CoA flux not shown
    • Single cancer-cell context
  9. 2025 High

    Provided the unifying biochemical mechanism, showing ER-resident TMEM120A partners with ACSL1/ACSL3 to drive acyl-CoA synthesis, fatty acid re-esterification, and lipid cycling during lipolysis.

    Evidence Co-IP of ACSL1/ACSL3, ER localization, adipocyte-specific knockout mice, and lipolysis/acyl-CoA synthesis and metabolic assays

    PMID:41423633

    Open questions at the time
    • Whether TMEM120A is catalytic or a CoA/acyl-CoA carrier/scaffold not resolved
    • Structural basis of ACSL interaction unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single CoA-binding ELOVL-like fold reconciles its distinct roles in ER lipid metabolism, nuclear genome organization, channel modulation, and STING trafficking remains unresolved.
  • No demonstration that CoA binding is mechanistically required for the channel-modulation, genome-organization, or STING functions
  • No enzymatic activity directly assigned to the CoA pocket
  • Relationship between ER and nuclear-envelope pools not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140104 molecular carrier activity 3 GO:0098772 molecular function regulator activity 2 GO:0008289 lipid binding 1
Localization
GO:0005635 nuclear envelope 2 GO:0005783 endoplasmic reticulum 2 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-4839726 Chromatin organization 2 R-HSA-168256 Immune System 1
Partners
ACSL1ACSL3PARKINPIEZO2PKD2STING

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 TACAN (TMEM120A) is expressed in a subset of nociceptors; heterologous expression increases mechanically evoked currents in cell lines; purification and reconstitution in synthetic lipids generates a functional ion channel; nociceptor-specific inducible knockout decreases mechanosensitivity and reduces behavioral responses to painful mechanical stimuli but not thermal or touch stimuli. Heterologous expression in cell lines, protein purification + lipid reconstitution, nociceptor-specific inducible knockout with behavioral assays and patch-clamp electrophysiology Cell Medium 32084332
2015 TMEM120A localizes to the nuclear envelope and is required for adipocyte differentiation; knockdown of TMEM120A alters expression of adipocyte differentiation genes (Gata3, Fasn, Glut4, Pparg, Adipoq) and reduces lipid accumulation in 3T3-L1 cells. siRNA knockdown in 3T3-L1 cells, qPCR for differentiation markers, Oil Red O staining and CARS microscopy for lipid accumulation, nuclear envelope localization by subcellular fractionation/microscopy PloS one Medium 26024229
2022 Adipocyte-specific knockout of Tmem120a disrupts fat genome organisation (repositioning of genes, enhancers, and miRNA loci between nuclear periphery and interior), broadly suppresses lipid metabolism pathway gene expression, induces myogenic gene expression, and causes a lipodystrophy syndrome in mice resembling human FPLD2 with insulin resistance and metabolic defects. Adipocyte-specific knockout mice, 3D genome organisation analysis, RNA-seq, metabolic phenotyping, comparison with FPLD2 patient cells Nature communications High 35027552
2021 Cryo-EM structure of human TMEM120A reveals a tightly packed dimer with N-terminal coiled-coil domain and C-terminal transmembrane domain (6 TMs forming an α-barrel); a coenzyme A (CoA) molecule is bound in a deep pocket within the TMD; structural homology to ELOVL fatty acid elongases; no clear structural features of an ion channel pore. Single-particle cryo-EM structure determination, CoA ligand identification by mass spectrometry (companion paper Niu et al.) eLife High 34374644 34374645 34409941
2021 TACAN (TMEM120A) does not exhibit mechanosensitive ion channel activity; at high protein concentrations, reconstituted TACAN produces heterogeneous conduction levels inconsistent with a bona fide channel and most consistent with lipid bilayer disruption; cryo-EM structure shows each protomer contains a CoA cofactor (confirmed by mass spectrometry) and is structurally related to fatty acid elongase ELOVL7. Cellular patch-clamp recording, membrane reconstitution electrophysiology, single-particle cryo-EM, native mass spectrometry eLife High 34374644
2021 TMEM120A expression alone is not sufficient to mediate poking- or stretch-induced currents in cells; cryo-EM structures reveal symmetrical homodimer with six membrane-spanning helices per monomer and a CoA molecule bound in a deep cavity via specific interactions with nearby residues; mutation of a central tryptophan involved in CoA binding dramatically reduces CoA binding affinity; TMEM120A adopts distinct conformations in CoA-bound vs. apo states. Patch-clamp electrophysiology (poking and stretch), single-particle cryo-EM (CoA-bound and apo states), site-directed mutagenesis of CoA-binding residue with binding affinity measurement eLife High 34409941
2022 TMEM120A co-expression specifically decreases amplitudes of mechanically activated PIEZO2 currents and increases their activation threshold in heterologous cells; TMEM120A did not inhibit PIEZO1 or TREK1; TMEM120A alone did not generate mechanically activated currents above background; siRNA knockdown of Tmem120a in mouse DRG neurons increased rapidly adapting mechanically activated current amplitudes and decreased their activation thresholds; Tmem120a and Piezo2 expression overlap in DRG neurons. Heterologous co-expression with patch-clamp electrophysiology, siRNA knockdown in primary DRG neurons with patch-clamp, in situ expression analysis The Journal of general physiology High 35819364
2022 TMEM120A overexpression inhibits Zika virus (ZIKV) replication; TMEM120A interacts with STING and promotes STING translocation from the ER to ERGIC; this enhances phosphorylation of downstream TBK1 and IRF3, resulting in expression of antiviral cytokines and interferon-stimulated genes; antiviral activity is STING-dependent. Genome-wide overexpression screen, Co-immunoprecipitation, subcellular fractionation/localization assay, TMEM120A knockdown and Tmem120a knockout (MEFs), phospho-western blot for TBK1/IRF3, cytokine/ISG expression analysis Nature communications High 35013224
2022 Cryo-EM structure of human TACAN shows each protomer has a transmembrane globular domain (6 helices) and intracellular domain (2 helices); molecular dynamics simulations suggest each protomer contains a putative ion conduction pore; single-point mutation M207A greatly increases membrane pressure-activated currents; each subunit binds one cholesterol molecule; wild-type hTACAN structure corresponds to a closed state. Single-particle cryo-EM, molecular dynamics simulation, site-directed mutagenesis (M207A) with patch-clamp electrophysiology, cholesterol binding identified from structure Cell reports Medium 35235791
2022 TACAN forms a complex with PKD2 in native renal cell lines; TACAN inhibits PKD2 channel activity (single-channel conductance and open probability) through direct physical interaction; TACAN N-terminal S1-containing fragment interacts with PKD2 C-terminal fragment (N580-L700) and TACAN C-terminal S6-containing fragment interacts with PKD2 N-terminal fragment; the PKD2-TACAN complex, but not PKD2 alone, confers mechanosensitivity; TACAN aggravates PKD2-dependent tail curvature and pronephric cysts in larval zebrafish. Co-immunoprecipitation in renal cell lines, two-electrode voltage clamp in Xenopus oocytes, patch-clamp in mammalian cells (single-channel conductance and open probability), fragment interaction mapping, zebrafish in vivo model The Journal of physiology High 36420836
2022 Parkin interacts with TACAN (TMEM120A) and knockdown of Parkin increases membrane trafficking of TACAN in sensory neurons; hen egg lysozyme increases Parkin expression (via NRF1-P300-mediated histone acetylation of the prkn promoter) and thereby decreases TACAN membrane trafficking, reducing static mechanical allodynia. Co-immunoprecipitation (Parkin-TACAN interaction), siRNA knockdown of Parkin with membrane trafficking assay, in vivo behavioral pain assays, chromatin immunoprecipitation (NRF1-P300 interaction at prkn promoter) Neuroscience Medium 35985504
2023 Nuclear localization of TMEM120A is required for its role in regulating chemotherapy sensitivity in colorectal cancer; nuclear TMEM120A sustains nuclear CoA levels, which influences nuclear acetyl-CoA levels and histone acetylation; direct inhibition of histone acetylation recapitulates TMEM120A depletion phenotype (increased chemosensitivity). CRISPR/Cas9 knockout, lentiviral overexpression of TMEM120A derivatives, cell fractionation, acid extraction of histones + western blot for histone acetylation, MTS cell viability assay Cancer chemotherapy and pharmacology Medium 37728615
2025 TMEM120A is an ER-resident CoA-binding protein; it interacts with ER-localized acyl-CoA synthetases ACSL1 and ACSL3 to promote long-chain acyl-CoA synthesis and channeling into the ER, facilitating fatty acid re-esterification and lipid cycling during lipolysis; by relieving acyl-CoA-mediated feedback inhibition of lipolysis, TMEM120A enhances lipid turnover and protects against ER stress; adipocyte-specific deletion impairs lipolysis-induced energy expenditure and exacerbates inflammation and metabolic dysfunction under high-fat diet. Co-immunoprecipitation (TMEM120A-ACSL1/ACSL3 interaction), ER localization by subcellular fractionation/imaging, adipocyte-specific Tmem120a knockout mice, metabolic phenotyping, lipolysis and acyl-CoA synthesis assays Nature communications High 41423633
2023 In C. elegans, tmem-120 (sole TMEM120A/B ortholog) is expressed in germline, embryos, and spermatheca; loss-of-function causes deformed germline, maternal sterility, and reduced brood size; loss of tmem-120 suppresses (alleviates) the brood size reduction and defective sperm navigation in pezo-1 (PIEZO ortholog) mutants, indicating a genetic epistatic interaction where tmem-120 acts as a negative regulator of pezo-1 function in reproduction. Genetic loss-of-function (full-length deletion), auxin-inducible degradation system for tissue-specific depletion, in vivo live imaging, double-mutant genetic epistasis analysis G3 (Bethesda, Md.) Medium 38051962

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 TACAN Is an Ion Channel Involved in Sensing Mechanical Pain. Cell 110 32084332
2015 TMEM120A and B: Nuclear Envelope Transmembrane Proteins Important for Adipocyte Differentiation. PloS one 61 26024229
2022 Genomic loci mispositioning in Tmem120a knockout mice yields latent lipodystrophy. Nature communications 41 35027552
2021 TMEM120A is a coenzyme A-binding membrane protein with structural similarities to ELOVL fatty acid elongase. eLife 31 34374645
2022 TMEM120A/TACAN inhibits mechanically activated PIEZO2 channels. The Journal of general physiology 29 35819364
2022 Gain-of-function genetic screening identifies the antiviral function of TMEM120A via STING activation. Nature communications 28 35013224
2021 Analysis of the mechanosensor channel functionality of TACAN. eLife 27 34374644
2021 TMEM120A contains a specific coenzyme A-binding site and might not mediate poking- or stretch-induced channel activities in cells. eLife 23 34409941
2020 Involvement of TACAN, a Mechanotransducing Ion Channel, in Inflammatory But Not Neuropathic Hyperalgesia in the Rat. The journal of pain 18 33232830
2022 Cryo-EM structure of the human TACAN in a closed state. Cell reports 15 35235791
2023 TMEM120A/TACAN: A putative regulator of ion channels, mechanosensation, and lipid metabolism. Channels (Austin, Tex.) 9 37523628
2022 Upregulation of TACAN in the trigeminal ganglion affects pain transduction in acute pulpitis. Archives of oral biology 7 36088852
2022 Regulation of PKD2 channel function by TACAN. The Journal of physiology 7 36420836
2023 TMEM120A-mediated regulation of chemotherapy sensitivity in colorectal cancer cells. Cancer chemotherapy and pharmacology 4 37728615
2022 The curious case of TMEM120A: Mechanosensor, fat regulator, or antiviral defender? BioEssays : news and reviews in molecular, cellular and developmental biology 3 35419854
2022 Hen Egg Lysozyme Alleviates Static Mechanical Pain Via NRF1-Parkin-TACAN Signaling Axis in Sensory Neurons. Neuroscience 3 35985504
2023 Transmembrane protein 120A (TMEM-120A/TACAN) coordinates with PIEZO channel during Caenorhabditis elegans reproductive regulation. G3 (Bethesda, Md.) 2 38051962
2025 TMEM120A maintains adipose tissue lipid homeostasis through ER CoA channeling. Nature communications 1 41423633
2024 Direct single-molecule detection of CoA-SH and ATP by the membrane proteins TMEM120A and TMEM120B. Nanoscale 1 38444242
2026 Biolayer Interferometry for Investigating Membrane Protein-Inhibitor Binding: TACAN Mutant and GsMTx4 As a Model System. Journal of visualized experiments : JoVE 0 42184262
2023 The expression and distribution of TACAN in human and rat bladders. Lower urinary tract symptoms 0 37649457

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