TMEM106A is a type II single-pass transmembrane protein of the TMEM106 family, a paralog of the lysosomal protein TMEM106B. It localizes to the plasma membrane, with a short N-terminal cytoplasmic segment and a large C-terminal extracellular/lumenal domain. Its best-characterized role is as a positive regulator of macrophage activation: it promotes polarization toward a pro-inflammatory M1-like state through MAPK and NF-kB signaling, up-regulating surface CD80, CD86, CD69 and MHC class II and inducing pro-inflammatory mediators such as TNF, IL1B, IL6, CCL2 and nitric oxide. TMEM106A also behaves as a candidate tumor suppressor in several epithelial cancers, where it is frequently inactivated; restoring its expression inhibits proliferation, migration and invasion, induces apoptosis, and represses epithelial-mesenchymal transition and PI3K/AKT/NF-kB signaling. The specific biochemical activity of the protein at the membrane is not yet defined.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005765 lysosomal membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Lysosomal-membrane localization is very likely paralog-derived over-propagation from TMEM106B, not a bona fide location for TMEM106A. Reason: This IBA sits on the TMEM106-family PAINT node (PANTHER:PTN002822587), whose lysosomal-membrane character derives from the extensively studied paralog TMEM106B, a well-characterized lysosomal membrane protein (the WITH/FROM even lists the human paralog UniProtKB:Q9NUM4 = TMEM106B). TMEM106A itself is curated by UniProt to the cell membrane (single-pass membrane protein, by similarity to mouse Q8VC04), and its documented function - macrophage activation via cell-surface signaling - operates at the plasma membrane. This is target-specific evidence that TMEM106A has diverged in localization from the family node, so lysosomal membrane should not be treated as a core location. Rather than assert an alternative id on an is_active_in row, flag it as over-annotated (paralog-derived); the plasma-membrane location is captured by the GO:0005886 annotations. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN002822587 · TMEM106 family node SUPPORTS SOURCE BUT NOT TARGET Lysosomal-membrane character of the node derives from the lysosomal paralog TMEM106B; localization does not transfer to TMEM106A. UniProtKB:Q9NUM4 · TMEM106B (human paralog) SUPPORTS SOURCE BUT NOT TARGET Well-characterized lysosomal membrane protein; source of the node's lysosomal-membrane localization, not applicable to the cell-surface paralog TMEM106A. |
| GO:0042116 macrophage activation | IBA GO_REF:0000033 | ACCEPT | Summary: Macrophage activation is the conserved core function of the TMEM106 family and is well supported for TMEM106A. Reason: This phylogenetically-inferred annotation reflects the conserved family role. TMEM106A activates macrophages / promotes M1 polarization via MAPK and NF-kB signaling (up-regulating CD80, CD86, CD69 and MHC class II and inducing TNF, IL1B, IL6, CCL2 and nitric oxide). The experimental grounding is in the mouse ortholog (UniProtKB:Q8VC04) and is carried to human TMEM106A by curator orthology transfer (UniProt FUNCTION, ECO:0000250|UniProtKB:Q8VC04) - not by a human macrophage assay in our cached literature. PMID:29131025 restates the point, but only in its BACKGROUND section as a summary of that prior mouse work; the study itself assays proliferation, migration and apoptosis in renal cancer cells and provides no independent macrophage-activation evidence. Retain as a core process on the orthology evidence, with the human-specific assay noted as an open gap. Supporting Evidence: PMID:29131025 TMEM106a is a conserved type II transmembrane protein which is a key factor to regulate macrophage activation. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma-membrane localization matches the UniProt-curated location for this type II single-pass membrane protein. Reason: TMEM106A is a type II single-pass transmembrane protein (TM 95-115) curated by UniProt as "Cell membrane; Single-pass membrane protein" (by similarity to mouse Q8VC04, SL-0039). Its characterized function operates at the macrophage cell surface, consistent with plasma-membrane residence. Accept as a core location. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Uninformative high-throughput interactome annotation (HuRI Y2H); 'protein binding' conveys no specific molecular function. Reason: This is a systematic yeast-two-hybrid screen from the human binary reference interactome (HuRI), not a focused study of TMEM106A biology. Per project guidelines the generic 'protein binding' (GO:0005515) term is uninformative about the actual molecular function, so the term is over-annotated. The WITH/FROM partner here is Q9BVX2 / TMEM106C, the same-family paralog also recovered by BioPlex AP-MS (PMID:33961781) - see that row for the family-heteromer reading. Not a core function; no informative replacement term can be justified from a high-throughput binary screen without direct validation. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Uninformative high-throughput interactome annotation (BioPlex AP-MS); 'protein binding' conveys no specific molecular function. Reason: This annotation derives from the proteome-scale BioPlex affinity-purification/MS network, a systematic interactome resource rather than a study of TMEM106A function. The generic 'protein binding' (GO:0005515) term is uninformative per project guidelines, so the term itself is over-annotated. The partner is not arbitrary, however. Q9BVX2 is TMEM106C, a same-family paralog, and it is the one interactor reproduced by two orthogonal methods - it appears in the WITH/FROM of both the HuRI Y2H row (PMID:32296183) and this BioPlex AP-MS row (PMID:33961781) - while UniProt records it at NbExp=5, the highest of the 11 listed interactions (all others are NbExp=3). A TMEM106A/TMEM106C family heteromer is therefore a real candidate worth testing, but 'protein binding' does not state it; a specific complex or heterodimerization term would need direct validation first. |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Correct but general - captures the MAPK/NF-kB cascade TMEM106A drives; a broad parent of its more specific role. Reason: TMEM106A signals through MAPK and NF-kB pathways to activate macrophages, so 'intracellular signal transduction' is accurate but is a high-level parent term that does not by itself capture the specific function. It is transferred by orthology from mouse Q8VC04. Keep as supporting/non-core context; the informative core is macrophage activation (GO:0042116). |
| GO:0042116 macrophage activation | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology-transferred macrophage activation; consistent with the conserved core function. Reason: Automatic orthology transfer from mouse Q8VC04, agreeing with the IBA and ISS macrophage-activation annotations and with the primary literature describing TMEM106A as a key regulator of macrophage activation (PMID:29131025). Retain as a core process. |
| GO:0035556 intracellular signal transduction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Correct but general - the MAPK/NF-kB signaling TMEM106A engages; a broad parent term, non-core. Reason: Manual sequence-similarity transfer from mouse Q8VC04. Accurate in that TMEM106A acts through intracellular MAPK and NF-kB cascades, but this is a high-level parent that does not capture the specific function. Keep as supporting/non-core; the core process is macrophage activation. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Plasma-membrane localization by curated sequence similarity to the mouse ortholog; matches UniProt. Reason: Manual ISS transfer from mouse Q8VC04, consistent with the UniProt-curated "Cell membrane; Single-pass membrane protein" location and with TMEM106A's cell-surface function in macrophage activation. Accept as a core location. |
| GO:0042116 macrophage activation | ISS GO_REF:0000024 | ACCEPT | Summary: Curated sequence-similarity transfer of the conserved macrophage-activation function; core process. Reason: Manual ISS transfer from the experimentally characterized mouse ortholog Q8VC04, the basis of the UniProt FUNCTION annotation, and concordant with the IBA/IEA macrophage-activation annotations and primary literature (PMID:29131025). Retain as the core biological process for TMEM106A. |
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Download this section (compressed HTML)Q: What is the molecular activity of TMEM106A at the plasma membrane — does it function as a receptor, co-receptor, signaling adaptor, or transporter, and what is its physiological ligand?
Q: How mechanistically distinct is TMEM106A from its lysosomal paralog TMEM106B, and to what extent (if any) does TMEM106A also access endolysosomal compartments in specific cell types?
Q: Is the reported tumor-suppressor phenotype a cell-intrinsic consequence of TMEM106A signaling or an indirect effect mediated through macrophage/immune activation in the tumor microenvironment?
Q: Does the Tmem106a locus contribute an out-of-frame C-terminal peptide to a human GSDMD:TMEM106A trans-spliced chimeric mRNA (as shown in mouse), and is that cryptic reading frame regulated or functional independently of the canonical TMEM106A protein?
Experiment: Define the TMEM106A interactome in macrophages with proximity labeling (BioID/TurboID) or co-immunoprecipitation-MS from differentiated macrophages, to move beyond generic binary-interactome hits toward a specific molecular function.
Experiment: Test the requirement of TMEM106A for M1 polarization directly using CRISPR knockout in human macrophages, reading out MAPK and NF-kB pathway activation, surface CD80/CD86/MHC-II, and cytokine output after pro-inflammatory stimulation.
Experiment: Determine subcellular localization at endogenous levels (knock-in tag or validated antibody) with confocal/immuno-EM to test plasma-membrane versus endolysosomal residence and directly address the paralog-derived lysosomal-membrane annotation.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The molecular activity of the canonical TMEM106A protein at the plasma membrane is undefined: it is not established whether it acts as a receptor, co-receptor, signaling adaptor, or transporter, and no physiological ligand or validated binding partner is known. The GO annotations capture a process (macrophage activation) and a location (plasma membrane) but no specific molecular function.
OPEN BIOLOGY MF_DARK
What is known: The conserved biological role (positive regulation of macrophage activation / M1 polarization via MAPK and NF-kB) and plasma-membrane localization are supported by the mouse ortholog and human studies; only the biochemical mechanism is dark.
Significance: Without a defined molecular function, TMEM106A cannot be placed mechanistically in the macrophage-activation pathway, and interpretation of its tumor-suppressor phenotype and of any therapeutic targeting remains speculative.
Gap: It is unknown whether the human Tmem106a locus participates in a GSDMD:TMEM106A trans-spliced chimeric mRNA. The chimera, and the out-of-frame C-terminal peptide it contributes, were characterized only in mouse; the existence, regulation, and function of a human orthologue are unestablished.
OPEN BIOLOGY BP_DARK
What is known: In mouse, inflammasome priming upregulates the Gsdmd-Tmem106a chimera and its product cooperates with GSDMD-NT at the plasma membrane; the gap is its conservation and relevance in human.
Significance: A functional human chimera would connect the Tmem106a locus to pyroptosis via a cryptic reading frame, distinct from the canonical TMEM106A macrophage role.
Provenance (the field's own admissions):
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