{"gene":"CMTM6","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2017,"finding":"CMTM6 binds PD-L1 at the plasma membrane and in recycling endosomes, preventing lysosome-mediated degradation of PD-L1 without affecting its transcription or maturation. CMTM6 depletion selectively reduces PD-L1 surface expression while leaving MHC class I unaffected, and reduces T-cell suppression in vitro and in vivo.","method":"Genome-wide CRISPR-Cas9 screen, co-immunoprecipitation, quantitative plasma membrane proteomics, co-localization by imaging, xenograft mouse models, T-cell suppression assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (CRISPR screen, Co-IP, quantitative proteomics, live imaging, in vivo models), replicated across two independent Nature papers simultaneously","pmids":["28813417"],"is_preprint":false},{"year":2017,"finding":"CMTM6 (and its closest family member CMTM4, but not other CMTM members) associates with PD-L1 protein at the cell surface, reduces PD-L1 ubiquitination, and increases PD-L1 protein half-life without affecting CD274 transcription, thereby enhancing the ability of PD-L1-expressing tumor cells to inhibit T cells. This function was confirmed by haploid genetic modifier screen and genetic complementation.","method":"Haploid genetic screen, haploid genetic modifier screen, genetic complementation, co-immunoprecipitation, ubiquitination assays, protein half-life measurements, T-cell inhibition co-culture assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — haploid genetic screens plus reciprocal Co-IP plus ubiquitination assays plus functional T-cell assays, replicated independently from PMID:28813417","pmids":["28813410"],"is_preprint":false},{"year":2023,"finding":"CMTM6 is critical for CD58 protein stability in addition to PD-L1. Competition between CD58 and PD-L1 for CMTM6 binding determines their rate of endosomal recycling over lysosomal degradation. Loss of CD58 leads to increased PD-L1 protein stabilization via freed CMTM6.","method":"CRISPR-Cas9 screen, proteomics, patient-derived co-cultures, humanized mouse models, single-cell RNA-sequencing, validation experiments","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR screen plus proteomics plus multiple orthogonal in vitro and in vivo validation methods in a single rigorous study","pmids":["37327789"],"is_preprint":false},{"year":2021,"finding":"CMTM6 physically interacts with p21 and prevents its ubiquitination mediated by SCFSKP2, CRL4CDT2, and APC/CCDC20 E3 ligase complexes in a cell-cycle-independent manner, thereby stabilizing p21 protein and leading to inactivation of the pRB/E2F pathway and G1/S phase arrest in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assays, in vitro and in vivo proliferation assays, cell cycle analysis, western blotting, xenograft models","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — Co-IP, ubiquitination assays, and multiple functional readouts (cell cycle, in vivo xenograft) in a single study from one lab","pmids":["35304440"],"is_preprint":false},{"year":2021,"finding":"CMTM6 physically interacts with and stabilizes vimentin, thereby promoting epithelial-mesenchymal transition (EMT) and increasing proliferation, migration, and invasion of hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, immunofluorescence, shRNA knockdown, overexpression, wound-healing assay, Matrigel invasion assay, xenograft model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal Co-IP plus functional assays plus in vivo model, single lab","pmids":["33757532"],"is_preprint":false},{"year":2021,"finding":"CMTM6 interaction with membrane-bound Enolase-1 (ENO-1) stabilizes ENO-1 expression, leading to activation of Wnt signaling mediated by AKT–glycogen synthase kinase-3β (GSK3β), thereby driving cisplatin resistance in oral squamous cell carcinoma.","method":"Global proteome profiling, stable knockdown and overexpression, patient-derived cell xenograft, transcriptome analysis, co-immunoprecipitation/interaction assays","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus functional rescue plus in vivo xenograft, single lab with multiple methods","pmids":["33434185"],"is_preprint":false},{"year":2022,"finding":"CMTM6 regulates ribosome biogenesis by inducing C-Myc expression (which promotes RNA polymerase I-mediated rDNA transcription) and by regulating AKT-mTORC1-dependent ribosome biogenesis and protein synthesis in cisplatin-resistant oral squamous cell carcinoma cells.","method":"RNA sequencing, CMTM6 knockdown/overexpression, rRNA transcription assays, nucleolar structure analysis, nude mice and zebrafish xenograft experiments","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus functional assays plus in vivo models, single lab","pmids":["36165231"],"is_preprint":false},{"year":2020,"finding":"CMTM6 is specifically localized to the adaxonal Schwann cell membrane (identified by label-free proteomics, STED-microscopy, and cryo-immuno electron-microscopy). Disruption of Cmtm6 expression in Schwann cells causes a substantial increase in axonal diameters without impairing myelin biogenesis, radial sorting, or axonal integrity, correlating with accelerated sensory nerve conduction and perturbed motor performance.","method":"Label-free proteomics, STED-microscopy, cryo-immuno electron-microscopy, conditional Schwann cell-specific knockout mice, electrophysiology","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal structural/imaging methods plus in vivo genetic knockout with defined functional phenotypes in a single rigorous study","pmids":["32908139"],"is_preprint":false},{"year":2020,"finding":"OSCC cell-secreted exosomal CMTM6 is transferred to macrophages and promotes M2-like macrophage polarization through activating ERK1/2 signaling.","method":"Ultracentrifugation-derived exosomes, qPCR, western blot, co-culture macrophage polarization assays, 4NQO-induced OSCC mouse model","journal":"Cancer immunology, immunotherapy : CII","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — exosome isolation, in vitro macrophage polarization assays, and in vivo mouse model; single lab with multiple complementary methods","pmids":["33104837"],"is_preprint":false},{"year":2020,"finding":"CMTM6 promotes cell proliferation and invasion in oral squamous cell carcinoma by physically interacting with Neuropilin-1 (NRP1). NRP1 silencing abrogates CMTM6-induced tumorigenesis. NRP1 is involved in the degradation process of CMTM6 (silencing NRP1 decreased CMTM6 stability).","method":"Co-immunoprecipitation, gain- and loss-of-function assays, wound-healing, Matrigel invasion assay, immunofluorescence","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional knockdown assays, single lab","pmids":["32642284"],"is_preprint":false},{"year":2021,"finding":"HuR RNA-binding protein stabilizes CMTM6 mRNA via direct association with AU-rich elements (AREs) in its 3'UTR, thereby upregulating CMTM6 and consequently increasing cell surface PD-L1 levels in cancer cells. HuR inhibition (MS-444) reduces CMTM6/PD-L1 and relieves T-cell immunosuppression.","method":"RNA immunoprecipitation, mRNA stability assays, HuR overexpression/knockdown, HuR inhibitor (MS-444), T-cell co-culture assays, in vivo allograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP plus mRNA stability plus functional in vitro and in vivo assays, single lab","pmids":["33649535"],"is_preprint":false},{"year":2023,"finding":"CMTM6 is physically associated with EGFR and co-localizes with EGFR in RAB11-positive recycling endosomes, preventing EGFR from lysosome-mediated degradation in NSCLC cells. A CMTM6-targeting nanobody blocks the CMTM6-EGFR interaction, reduces EGFR protein levels, and inhibits TKI-resistant NSCLC growth in vitro and in vivo.","method":"Co-immunoprecipitation, co-localization imaging, shRNA knockdown, nanobody development, cell-line-derived and patient-derived xenograft models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus imaging plus functional in vivo PDX models, single lab","pmids":["40521789"],"is_preprint":false},{"year":2023,"finding":"CMTM6 promotes HCC cell proliferation by physically interacting with β-catenin and stabilizing it by preventing its ubiquitination, thereby activating the β-catenin/Wnt pathway. Cmtm6 knockout mice showed inhibited HCC formation in DEN and DEN/CCl4-induced primary liver cancer models.","method":"Co-immunoprecipitation, ubiquitination assay, Cmtm6 knockout mice (primary liver cancer models), HCC cell line overexpression/knockdown","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and in vivo knockout model; single lab","pmids":["38101607"],"is_preprint":false},{"year":2024,"finding":"CMTM6 forms a complex with Glut1 and Rab11 in endosomes of colorectal cancer cells, and this complex is required for Rab11-dependent transport of Glut1 to the plasma membrane, protecting Glut1 from lysosomal degradation and thereby enabling the Warburg effect and supporting liver metastasis.","method":"shRNA knockdown, co-immunoprecipitation, endosomal fractionation, glucose uptake/glycolysis assays, subcutaneous and liver metastasis mouse models, multiomics (transcriptomics, proteomics)","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional assays, and in vivo metastasis models with multiomics, single lab","pmids":["39218981"],"is_preprint":false},{"year":2022,"finding":"Loss of CMTM6 in clear cell renal cell carcinoma triggers aberrant activation of the DNA damage response, resulting in micronucleus formation and G2/M checkpoint arrest, leading to cellular senescence with upregulation of chemokines and cytokines (SASP), and increased CD4+ and CD8+ T-cell infiltration.","method":"CMTM6 depletion in vitro and in vivo (xenograft, syngeneic graft mouse models), DNA damage assays, cell cycle analysis, micronucleus detection, cytokine profiling, flow cytometry","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO/KD with multiple cellular phenotype readouts plus in vivo syngeneic models, single lab","pmids":["35024247"],"is_preprint":false},{"year":2024,"finding":"EP300-mediated H3K27ac modification drives transcriptional activation of CMTM6 in pancreatic ductal adenocarcinoma. CMTM6, in turn, maintains IGF2BP1 expression by preventing its ubiquitination. IGF2BP1 (as an m6A reader) stabilizes EP300 and MYC mRNAs, forming a positive feedback loop (EP300-CMTM6-IGF2BP1) that enhances tumor stemness and gemcitabine resistance.","method":"Gemcitabine-resistant PDAC cell lines and PDX models, RNA sequencing, multi-omics, ChIP-seq (H3K27ac), ubiquitination assay, IGF2BP1 RIP, EP300 inhibitor (inobrodib) combination experiments","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics plus ubiquitination assay plus PDX models, single lab","pmids":["39488785"],"is_preprint":false},{"year":2022,"finding":"A stable membrane-bound full-length CMTM6-PD-L1 complex was assembled using LMNG detergent and amphipol A8-35. Biochemical analysis showed that CMTM6 greatly enhances PD-1 binding to PD-L1 and delays dissociation of PD-1/PD-L1, thereby affecting immunosuppressive and anti-apoptotic signaling. An anti-CMTM6 nanobody (1A5) derived from this complex decreased T-cell immunosuppression and inhibited tumor growth in CT26 tumor-bearing mice in a CD8+ T-cell-dependent manner.","method":"In vitro reconstitution of CMTM6-PD-L1 complex, binding kinetics (SPR/BLI-type), camel immune repertoire nanobody generation, T-cell co-culture assays, CT26 syngeneic tumor model","journal":"Acta pharmacologica Sinica","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted full-length membrane complex, binding kinetics, and in vivo functional validation; single lab but multiple rigorous methods","pmids":["36418428"],"is_preprint":false},{"year":2026,"finding":"FLT3 physically interacts with CMTM6 within their transmembrane domains (in a phosphorylation-independent manner) and enhances CMTM6 protein stability in AML cells, increasing PD-L1 surface expression. FLT3 inhibition reduces CMTM6 and PD-L1 expression. Cmtm6-deficient FLT3-ITD+ leukemia cells showed prolonged survival, reduced leukemia burden, and enhanced T-cell effector function in allogeneic hematopoietic cell transplantation mouse models.","method":"Co-immunoprecipitation (transmembrane domain interaction), FLT3 inhibition, Cmtm6 knockout in FLT3-ITD+ leukemia cells, three allogeneic HCT mouse models, flow cytometry (T-cell exhaustion markers), primary patient AML cell validation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus multiple in vivo mouse models plus primary patient cell validation, single lab with multiple orthogonal methods","pmids":["41043134"],"is_preprint":false},{"year":2026,"finding":"Mouse CMTM6 strongly associates with the death receptor FAS (identified by mass spectrometry) and negatively regulates FAS surface expression in mice. CMTM6 deletion increases FAS plasma membrane localization and sensitizes murine cells to FAS ligand-induced cytotoxicity. This interaction is absent in human cells due to differences in three amino acids at the boundary of the FAS extracellular and transmembrane domains.","method":"Mass spectrometry interactome, co-immunoprecipitation, FAS surface expression by flow cytometry, CMTM6 deletion, FAS ligand cytotoxicity assays, human-mouse domain comparison and mutagenesis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — MS identification plus Co-IP plus functional FAS ligand assays plus domain-level mechanistic explanation, single lab with multiple methods","pmids":["41634378"],"is_preprint":false},{"year":2021,"finding":"In ANCA-associated vasculitis (AAV), monocytes have reduced CMTM6 expression, leading to enhanced lysosomal degradation of PD-L1, lower PD-L1 surface expression, and increased T-cell stimulatory capacity. Inhibiting lysosomal function corrected this phenotype by increasing PD-L1.","method":"In vitro co-culture of patient monocytes, surface PD-L1 measurement, lysosomal inhibitor experiments, CD4+ T-cell activation/proliferation assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — patient monocyte co-cultures plus pharmacological rescue of lysosomal pathway, mechanistic link established, single lab","pmids":["34108971"],"is_preprint":false},{"year":2025,"finding":"MAVS co-localizes with and stabilizes CMTM6, shielding it from lysosomal degradation. Disruption of the MAVS-CMTM6 axis provokes mitochondrial dysfunction and ROS accumulation, leading to senescence and a SASP marked by CCL3, which recruits CD8+ T cells for antitumor immunity in renal carcinoma.","method":"Co-immunoprecipitation, mass spectrometry, co-localization imaging, MAVS-deficient mouse models, ROS scavenging (NAC), CD8+ T-cell depletion, flow cytometry, PD-1 blockade combination","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mass spectrometry plus in vivo MAVS-KO models plus pharmacological rescue, single lab","pmids":["41469142"],"is_preprint":false},{"year":2024,"finding":"CMTM6 inhibits ocular surface inflammation and maintains corneal epithelial barrier function via suppression of the NF-κB p65 signaling pathway. CMTM6 knockout mice showed more severe dry eye disease, barrier disruption, and reduced ZO-1 expression. NF-κB p65 inhibition reversed the excessive inflammation caused by CMTM6 knockdown.","method":"Cmtm6 knockout mice, siRNA/shRNA knockdown, lentiviral overexpression, NF-κB p65 inhibitor (JSH-23), ECIS barrier assay, immunofluorescence (ZO-1), flow cytometry, cytometric bead array","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model plus pharmacological NF-κB rescue plus multiple barrier function readouts, single lab","pmids":["38165704"],"is_preprint":false},{"year":2026,"finding":"CMTM6 interacts with Nectin-2 (PVRL2) via RAB14/RAB11-mediated endosomal trafficking, inhibiting Nectin-2 degradation through both lysosomal and proteasomal pathways. CMTM6 knockdown enhances NK cell infiltration into gastric tumors and suppresses tumor growth.","method":"Proteomic analysis, co-immunoprecipitation, cycloheximide chase assay, lysosomal/proteasomal inhibitors, animal models of gastric cancer, tumor tissue microarray","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP plus CHX chase plus pharmacological degradation pathway dissection plus in vivo model, single lab","pmids":["41840509"],"is_preprint":false},{"year":2026,"finding":"CMTM6 maintains TAK1 stability by inhibiting its ubiquitin-proteasome degradation in fibroblast-like synoviocytes (FLSs), thereby activating the TNF/TNFR pathway and downstream NF-κB/MAPK signaling and promoting synovial inflammation in rheumatoid arthritis. AAV-mediated Cmtm6 knockdown attenuated arthritis severity in collagen-induced arthritis mice.","method":"Co-immunoprecipitation, immunofluorescence, ubiquitination assay, cycloheximide (CHX) assay, RNA-sequencing, AAV-shCmtm6 treatment in CIA mice, micro-CT and histology","journal":"Journal of orthopaedic translation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination/CHX assays plus in vivo CIA model, single lab with multiple methods","pmids":["41836582"],"is_preprint":false},{"year":2023,"finding":"CMTM6 knockdown in HNSCC cells reduced nuclear β-catenin expression, inhibited stem cell-like properties, TGFβ-induced EMT, and cell proliferation. CMTM6 silencing also decreased PD-L1, delayed tumor growth in vivo, and increased CD8+ and CD4+ T-cell infiltration while reducing exhausted T-cell populations.","method":"shRNA knockdown, western blotting, flow cytometry, T-cell infiltration analysis in syngeneic SCC7 tumor model","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — shRNA KD with multiple cellular and in vivo readouts, single lab","pmids":["31771985"],"is_preprint":false},{"year":2021,"finding":"CMTM6 and CMTM7 are co-induced with EMT (driven by SNAI1) in breast cancer cells and together regulate surface PD-L1 expression. Dual knockdown of CMTM6 and CMTM7 significantly decreased PD-L1 surface expression more than either alone in mesenchymal breast cancer cells.","method":"SNAI1-inducible EMT model in MCF-7 cells, siRNA knockdown of CMTM6 and/or CMTM7, flow cytometry for surface PD-L1","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — dual siRNA knockdown plus inducible EMT model, single lab","pmids":["33803139"],"is_preprint":false}],"current_model":"CMTM6 is a ubiquitously expressed type-3 transmembrane protein that acts as a broad stabilizer of multiple cell-surface proteins—most notably PD-L1, but also CD58, EGFR, HER2, Glut1, Nectin-2, vimentin, p21, TAK1, β-catenin, ENO-1, and (in mice) FAS—by co-localizing with them in recycling endosomes and preventing their ubiquitin-mediated lysosomal or proteasomal degradation, thereby controlling immune checkpoint signaling, receptor trafficking, metabolic reprogramming, cytoskeletal dynamics, and cell-cycle progression; it is also stabilized by binding partners such as MAVS and FLT3 via transmembrane domain interactions, and its expression is post-transcriptionally regulated by HuR binding to AU-rich elements in its 3'UTR."},"narrative":{"mechanistic_narrative":"CMTM6 is a transmembrane protein that functions as a broad post-translational stabilizer of cell-surface and signaling proteins by binding them in recycling endosomes and diverting them from ubiquitin-mediated degradation, with central roles in immune checkpoint control, receptor trafficking, and tumor biology [PMID:28813417, PMID:28813410]. Its founding and best-defined function is stabilization of PD-L1: CMTM6 (and its closest family member CMTM4) associates with PD-L1 at the plasma membrane and in recycling endosomes, reduces PD-L1 ubiquitination, extends its half-life without altering CD274 transcription, and thereby sustains tumor-cell suppression of T cells [PMID:28813417, PMID:28813410]. CMTM6 acts as a shared, rate-limiting chaperone for which client proteins compete: CD58 and PD-L1 compete for CMTM6 binding, so loss of one client frees CMTM6 to stabilize the other [PMID:37327789]. Structurally, CMTM6 forms a membrane-bound complex with full-length PD-L1 that enhances PD-1 binding and delays PD-1/PD-L1 dissociation, and a CMTM6-targeting nanobody relieves T-cell immunosuppression and inhibits tumor growth in a CD8+ T-cell-dependent manner [PMID:36418428]. Beyond PD-L1, CMTM6 stabilizes a wide range of clients by the same endosomal anti-degradation logic—EGFR via RAB11-positive recycling endosomes [PMID:40521789], Glut1 in a Rab11-dependent complex to support glycolysis and metastasis [PMID:39218981], Nectin-2/PVRL2 via RAB14/RAB11 trafficking to restrain NK-cell attack [PMID:41840509], β-catenin [PMID:38101607], the cell-cycle inhibitor p21 [PMID:35304440], vimentin [PMID:33757532], and TAK1 [PMID:41836582]—linking it to receptor signaling, metabolic reprogramming, epithelial-mesenchymal transition, and inflammatory pathways. CMTM6 itself is regulated post-transcriptionally and by partner binding: HuR stabilizes CMTM6 mRNA through AU-rich elements in its 3'UTR [PMID:33649535], while MAVS [PMID:41469142] and the receptor tyrosine kinase FLT3, via a transmembrane-domain interaction, shield CMTM6 protein from degradation [PMID:41043134]. Loss of CMTM6 can trigger DNA damage response, senescence, and a SASP that recruits T cells [PMID:35024247, PMID:41469142]. CMTM6 also has non-tumor physiological roles, including maintaining adaxonal Schwann cell membrane structure and constraining axonal diameter [PMID:32908139], suppressing ocular surface inflammation via NF-κB p65 [PMID:38165704], and, in mice but not humans, negatively regulating surface FAS to limit FAS-ligand cytotoxicity [PMID:41634378].","teleology":[{"year":2017,"claim":"Established the founding function of CMTM6 by answering how PD-L1 protein is maintained at the cell surface independent of transcription, identifying CMTM6 as the rate-limiting stabilizer of the immune checkpoint.","evidence":"Genome-wide CRISPR and haploid genetic screens, Co-IP, ubiquitination and half-life assays, quantitative membrane proteomics, and T-cell suppression assays in two independent studies","pmids":["28813417","28813410"],"confidence":"High","gaps":["Did not resolve the E3 ligase machinery from which CMTM6 protects PD-L1","Mechanism of the CMTM6-PD-L1 transmembrane interaction not structurally defined"]},{"year":2020,"claim":"Revealed a physiological, non-immune role for CMTM6 by localizing it to the adaxonal Schwann cell membrane and showing it constrains axonal diameter, demonstrating function beyond checkpoint biology.","evidence":"Label-free proteomics, STED and cryo-immuno EM, and Schwann cell-specific conditional knockout mice with electrophysiology","pmids":["32908139"],"confidence":"High","gaps":["Molecular client mediating axonal diameter control not identified","Connection to the endosomal stabilization mechanism not established in this tissue"]},{"year":2020,"claim":"Extended CMTM6 into the tumor microenvironment as a transferable factor, showing exosomal CMTM6 polarizes macrophages and that CMTM6 promotes OSCC via NRP1 interaction.","evidence":"Exosome isolation with macrophage co-culture and 4NQO mouse model; Co-IP and gain/loss-of-function invasion assays","pmids":["33104837","32642284"],"confidence":"Medium","gaps":["NRP1-dependent CMTM6 degradation mechanism not dissected","Exosomal ERK1/2 activation mechanism downstream of CMTM6 unresolved"]},{"year":2021,"claim":"Generalized the stabilization mechanism beyond surface receptors by showing CMTM6 protects intracellular and cytoskeletal clients (p21, vimentin, ENO-1) from degradation, linking it to cell-cycle, EMT, and metabolic/Wnt signaling.","evidence":"Co-IP, ubiquitination assays, cell cycle analysis, proteomics, and xenograft models across HCC and OSCC","pmids":["35304440","33757532","33434185"],"confidence":"Medium","gaps":["Whether these are direct binding clients or indirect effects not fully separated","Specificity determinants for the diverse client set unknown"]},{"year":2021,"claim":"Identified upstream regulation of CMTM6 itself, answering how its abundance is set, via HuR-mediated mRNA stabilization and EMT/SNAI1-driven co-induction with CMTM7.","evidence":"RNA-IP, mRNA stability assays, HuR inhibitor, and SNAI1-inducible EMT model with dual siRNA knockdown","pmids":["33649535","33803139"],"confidence":"Medium","gaps":["Relative contribution of transcriptional vs post-transcriptional control across tissues unknown","Functional redundancy boundary between CMTM6 and CMTM7 not mapped"]},{"year":2022,"claim":"Provided structural and biochemical mechanism by reconstituting the membrane CMTM6-PD-L1 complex and showing CMTM6 directly enhances PD-1/PD-L1 affinity, and demonstrated loss-of-CMTM6 triggers DDR-driven senescence.","evidence":"In vitro reconstitution with binding kinetics and anti-CMTM6 nanobody in CT26 mice; CMTM6 depletion with DNA damage and micronucleus assays in ccRCC","pmids":["36418428","35024247"],"confidence":"High","gaps":["High-resolution structure of the complex not determined","Mechanism linking CMTM6 loss to DNA damage response not defined"]},{"year":2023,"claim":"Defined CMTM6 as a shared limiting chaperone subject to client competition, and extended its trafficking-based stabilization to EGFR and β-catenin with therapeutic targeting.","evidence":"CRISPR screen, proteomics, humanized mouse and PDX models; Co-IP, RAB11 co-localization imaging, ubiquitination assays, and CMTM6-targeting nanobody","pmids":["37327789","40521789","38101607","31771985"],"confidence":"High","gaps":["Hierarchy of client affinities not quantified","How a single protein selects among competing clients spatially unresolved"]},{"year":2024,"claim":"Broadened the trafficking mechanism to a metabolic transporter and to transcription/epigenetic feedback, with Glut1 stabilization via a Rab11 complex and an EP300-CMTM6-IGF2BP1 loop.","evidence":"Endosomal fractionation, Co-IP, glycolysis assays, metastasis models; ChIP-seq, ubiquitination assay, RIP, and PDX models","pmids":["39218981","39488785"],"confidence":"Medium","gaps":["Direct vs scaffold role of CMTM6 within the Rab11 transport complex unclear","Whether IGF2BP1 stabilization is direct binding not established"]},{"year":2024,"claim":"Established CMTM6 as a homeostatic anti-inflammatory factor at epithelial barriers, showing it suppresses NF-κB p65 to maintain corneal epithelial integrity.","evidence":"Cmtm6 knockout mice, NF-κB inhibitor rescue, barrier (ECIS) and ZO-1 immunofluorescence assays","pmids":["38165704"],"confidence":"Medium","gaps":["Molecular client linking CMTM6 to NF-κB suppression not identified","Whether this involves the endosomal stabilization mechanism unknown"]},{"year":2025,"claim":"Identified partners that stabilize CMTM6 protein itself, with MAVS shielding CMTM6 from lysosomal degradation and the MAVS-CMTM6 axis governing mitochondrial stress and antitumor immunity.","evidence":"Co-IP, mass spectrometry, MAVS-deficient mouse models, ROS scavenging, and CD8+ T-cell depletion","pmids":["41469142"],"confidence":"Medium","gaps":["Subcellular site of MAVS-CMTM6 interaction not pinned down","How CMTM6 loss provokes mitochondrial dysfunction mechanistically unresolved"]},{"year":2026,"claim":"Defined transmembrane-domain-mediated partner control and species-specific clients, with FLT3 stabilizing CMTM6 in AML, CMTM6 stabilizing Nectin-2 and TAK1, and a mouse-specific FAS interaction.","evidence":"Transmembrane-domain Co-IP, allogeneic HCT and CIA mouse models, CHX chase, mass spectrometry interactome, and human-mouse domain mutagenesis","pmids":["41043134","41840509","41836582","41634378"],"confidence":"High","gaps":["Structural basis of transmembrane-domain recognition across partners not resolved","General rules predicting which receptors CMTM6 stabilizes vs which stabilize CMTM6 unknown"]},{"year":null,"claim":"It remains unknown what structural and biochemical features determine CMTM6 client selectivity and the directionality of stabilization, and which ubiquitin ligases CMTM6 antagonizes for each client.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying structural model of CMTM6 client recognition","Cognate E3 ligases for most clients unidentified","Quantitative client-competition hierarchy not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,16]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,1,11,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,11,13,22]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,16]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[11,13,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,12,23]}],"complexes":["CMTM6-PD-L1 complex","CMTM6-Glut1-Rab11 complex"],"partners":["CD274","CD58","EGFR","SLC2A1","PVRL2","CTNNB1","FLT3","MAVS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NX76","full_name":"CKLF-like MARVEL transmembrane domain-containing protein 6","aliases":["Chemokine-like factor superfamily member 6"],"length_aa":183,"mass_kda":20.4,"function":"Master regulator of recycling and plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. Associates with both constitutive and IFNG-induced PD-L1/CD274 at recycling endosomes, where it protects PD-L1/CD274 from being targeted for lysosomal degradation, likely by preventing its STUB1-mediated ubiquitination. May stabilize PD-L1/CD274 expression on antigen presenting cells and potentiates inhibitory signaling by PDCD1/CD279, its receptor on T-cells, ultimately triggering T-cell anergy","subcellular_location":"Cell membrane; Early endosome membrane; Recycling endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9NX76/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CMTM6","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CMTM6","total_profiled":1310},"omim":[{"mim_id":"607889","title":"CKLF-LIKE MARVEL TRANSMEMBRANE DOMAIN-CONTAINING 6; CMTM6","url":"https://www.omim.org/entry/607889"},{"mim_id":"607887","title":"CKLF-LIKE MARVEL TRANSMEMBRANE DOMAIN-CONTAINING 4; 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CMTM6 depletion selectively reduces PD-L1 surface expression while leaving MHC class I unaffected, and reduces T-cell suppression in vitro and in vivo.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, co-immunoprecipitation, quantitative plasma membrane proteomics, co-localization by imaging, xenograft mouse models, T-cell suppression assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (CRISPR screen, Co-IP, quantitative proteomics, live imaging, in vivo models), replicated across two independent Nature papers simultaneously\",\n      \"pmids\": [\"28813417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CMTM6 (and its closest family member CMTM4, but not other CMTM members) associates with PD-L1 protein at the cell surface, reduces PD-L1 ubiquitination, and increases PD-L1 protein half-life without affecting CD274 transcription, thereby enhancing the ability of PD-L1-expressing tumor cells to inhibit T cells. This function was confirmed by haploid genetic modifier screen and genetic complementation.\",\n      \"method\": \"Haploid genetic screen, haploid genetic modifier screen, genetic complementation, co-immunoprecipitation, ubiquitination assays, protein half-life measurements, T-cell inhibition co-culture assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — haploid genetic screens plus reciprocal Co-IP plus ubiquitination assays plus functional T-cell assays, replicated independently from PMID:28813417\",\n      \"pmids\": [\"28813410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CMTM6 is critical for CD58 protein stability in addition to PD-L1. Competition between CD58 and PD-L1 for CMTM6 binding determines their rate of endosomal recycling over lysosomal degradation. Loss of CD58 leads to increased PD-L1 protein stabilization via freed CMTM6.\",\n      \"method\": \"CRISPR-Cas9 screen, proteomics, patient-derived co-cultures, humanized mouse models, single-cell RNA-sequencing, validation experiments\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR screen plus proteomics plus multiple orthogonal in vitro and in vivo validation methods in a single rigorous study\",\n      \"pmids\": [\"37327789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CMTM6 physically interacts with p21 and prevents its ubiquitination mediated by SCFSKP2, CRL4CDT2, and APC/CCDC20 E3 ligase complexes in a cell-cycle-independent manner, thereby stabilizing p21 protein and leading to inactivation of the pRB/E2F pathway and G1/S phase arrest in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, in vitro and in vivo proliferation assays, cell cycle analysis, western blotting, xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — Co-IP, ubiquitination assays, and multiple functional readouts (cell cycle, in vivo xenograft) in a single study from one lab\",\n      \"pmids\": [\"35304440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CMTM6 physically interacts with and stabilizes vimentin, thereby promoting epithelial-mesenchymal transition (EMT) and increasing proliferation, migration, and invasion of hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, shRNA knockdown, overexpression, wound-healing assay, Matrigel invasion assay, xenograft model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal Co-IP plus functional assays plus in vivo model, single lab\",\n      \"pmids\": [\"33757532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CMTM6 interaction with membrane-bound Enolase-1 (ENO-1) stabilizes ENO-1 expression, leading to activation of Wnt signaling mediated by AKT–glycogen synthase kinase-3β (GSK3β), thereby driving cisplatin resistance in oral squamous cell carcinoma.\",\n      \"method\": \"Global proteome profiling, stable knockdown and overexpression, patient-derived cell xenograft, transcriptome analysis, co-immunoprecipitation/interaction assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus functional rescue plus in vivo xenograft, single lab with multiple methods\",\n      \"pmids\": [\"33434185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CMTM6 regulates ribosome biogenesis by inducing C-Myc expression (which promotes RNA polymerase I-mediated rDNA transcription) and by regulating AKT-mTORC1-dependent ribosome biogenesis and protein synthesis in cisplatin-resistant oral squamous cell carcinoma cells.\",\n      \"method\": \"RNA sequencing, CMTM6 knockdown/overexpression, rRNA transcription assays, nucleolar structure analysis, nude mice and zebrafish xenograft experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus functional assays plus in vivo models, single lab\",\n      \"pmids\": [\"36165231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CMTM6 is specifically localized to the adaxonal Schwann cell membrane (identified by label-free proteomics, STED-microscopy, and cryo-immuno electron-microscopy). Disruption of Cmtm6 expression in Schwann cells causes a substantial increase in axonal diameters without impairing myelin biogenesis, radial sorting, or axonal integrity, correlating with accelerated sensory nerve conduction and perturbed motor performance.\",\n      \"method\": \"Label-free proteomics, STED-microscopy, cryo-immuno electron-microscopy, conditional Schwann cell-specific knockout mice, electrophysiology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal structural/imaging methods plus in vivo genetic knockout with defined functional phenotypes in a single rigorous study\",\n      \"pmids\": [\"32908139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OSCC cell-secreted exosomal CMTM6 is transferred to macrophages and promotes M2-like macrophage polarization through activating ERK1/2 signaling.\",\n      \"method\": \"Ultracentrifugation-derived exosomes, qPCR, western blot, co-culture macrophage polarization assays, 4NQO-induced OSCC mouse model\",\n      \"journal\": \"Cancer immunology, immunotherapy : CII\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — exosome isolation, in vitro macrophage polarization assays, and in vivo mouse model; single lab with multiple complementary methods\",\n      \"pmids\": [\"33104837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CMTM6 promotes cell proliferation and invasion in oral squamous cell carcinoma by physically interacting with Neuropilin-1 (NRP1). NRP1 silencing abrogates CMTM6-induced tumorigenesis. NRP1 is involved in the degradation process of CMTM6 (silencing NRP1 decreased CMTM6 stability).\",\n      \"method\": \"Co-immunoprecipitation, gain- and loss-of-function assays, wound-healing, Matrigel invasion assay, immunofluorescence\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional knockdown assays, single lab\",\n      \"pmids\": [\"32642284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HuR RNA-binding protein stabilizes CMTM6 mRNA via direct association with AU-rich elements (AREs) in its 3'UTR, thereby upregulating CMTM6 and consequently increasing cell surface PD-L1 levels in cancer cells. HuR inhibition (MS-444) reduces CMTM6/PD-L1 and relieves T-cell immunosuppression.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assays, HuR overexpression/knockdown, HuR inhibitor (MS-444), T-cell co-culture assays, in vivo allograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP plus mRNA stability plus functional in vitro and in vivo assays, single lab\",\n      \"pmids\": [\"33649535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CMTM6 is physically associated with EGFR and co-localizes with EGFR in RAB11-positive recycling endosomes, preventing EGFR from lysosome-mediated degradation in NSCLC cells. A CMTM6-targeting nanobody blocks the CMTM6-EGFR interaction, reduces EGFR protein levels, and inhibits TKI-resistant NSCLC growth in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging, shRNA knockdown, nanobody development, cell-line-derived and patient-derived xenograft models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus imaging plus functional in vivo PDX models, single lab\",\n      \"pmids\": [\"40521789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CMTM6 promotes HCC cell proliferation by physically interacting with β-catenin and stabilizing it by preventing its ubiquitination, thereby activating the β-catenin/Wnt pathway. Cmtm6 knockout mice showed inhibited HCC formation in DEN and DEN/CCl4-induced primary liver cancer models.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Cmtm6 knockout mice (primary liver cancer models), HCC cell line overexpression/knockdown\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and in vivo knockout model; single lab\",\n      \"pmids\": [\"38101607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CMTM6 forms a complex with Glut1 and Rab11 in endosomes of colorectal cancer cells, and this complex is required for Rab11-dependent transport of Glut1 to the plasma membrane, protecting Glut1 from lysosomal degradation and thereby enabling the Warburg effect and supporting liver metastasis.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation, endosomal fractionation, glucose uptake/glycolysis assays, subcutaneous and liver metastasis mouse models, multiomics (transcriptomics, proteomics)\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional assays, and in vivo metastasis models with multiomics, single lab\",\n      \"pmids\": [\"39218981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of CMTM6 in clear cell renal cell carcinoma triggers aberrant activation of the DNA damage response, resulting in micronucleus formation and G2/M checkpoint arrest, leading to cellular senescence with upregulation of chemokines and cytokines (SASP), and increased CD4+ and CD8+ T-cell infiltration.\",\n      \"method\": \"CMTM6 depletion in vitro and in vivo (xenograft, syngeneic graft mouse models), DNA damage assays, cell cycle analysis, micronucleus detection, cytokine profiling, flow cytometry\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO/KD with multiple cellular phenotype readouts plus in vivo syngeneic models, single lab\",\n      \"pmids\": [\"35024247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EP300-mediated H3K27ac modification drives transcriptional activation of CMTM6 in pancreatic ductal adenocarcinoma. CMTM6, in turn, maintains IGF2BP1 expression by preventing its ubiquitination. IGF2BP1 (as an m6A reader) stabilizes EP300 and MYC mRNAs, forming a positive feedback loop (EP300-CMTM6-IGF2BP1) that enhances tumor stemness and gemcitabine resistance.\",\n      \"method\": \"Gemcitabine-resistant PDAC cell lines and PDX models, RNA sequencing, multi-omics, ChIP-seq (H3K27ac), ubiquitination assay, IGF2BP1 RIP, EP300 inhibitor (inobrodib) combination experiments\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics plus ubiquitination assay plus PDX models, single lab\",\n      \"pmids\": [\"39488785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A stable membrane-bound full-length CMTM6-PD-L1 complex was assembled using LMNG detergent and amphipol A8-35. Biochemical analysis showed that CMTM6 greatly enhances PD-1 binding to PD-L1 and delays dissociation of PD-1/PD-L1, thereby affecting immunosuppressive and anti-apoptotic signaling. An anti-CMTM6 nanobody (1A5) derived from this complex decreased T-cell immunosuppression and inhibited tumor growth in CT26 tumor-bearing mice in a CD8+ T-cell-dependent manner.\",\n      \"method\": \"In vitro reconstitution of CMTM6-PD-L1 complex, binding kinetics (SPR/BLI-type), camel immune repertoire nanobody generation, T-cell co-culture assays, CT26 syngeneic tumor model\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted full-length membrane complex, binding kinetics, and in vivo functional validation; single lab but multiple rigorous methods\",\n      \"pmids\": [\"36418428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FLT3 physically interacts with CMTM6 within their transmembrane domains (in a phosphorylation-independent manner) and enhances CMTM6 protein stability in AML cells, increasing PD-L1 surface expression. FLT3 inhibition reduces CMTM6 and PD-L1 expression. Cmtm6-deficient FLT3-ITD+ leukemia cells showed prolonged survival, reduced leukemia burden, and enhanced T-cell effector function in allogeneic hematopoietic cell transplantation mouse models.\",\n      \"method\": \"Co-immunoprecipitation (transmembrane domain interaction), FLT3 inhibition, Cmtm6 knockout in FLT3-ITD+ leukemia cells, three allogeneic HCT mouse models, flow cytometry (T-cell exhaustion markers), primary patient AML cell validation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus multiple in vivo mouse models plus primary patient cell validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41043134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Mouse CMTM6 strongly associates with the death receptor FAS (identified by mass spectrometry) and negatively regulates FAS surface expression in mice. CMTM6 deletion increases FAS plasma membrane localization and sensitizes murine cells to FAS ligand-induced cytotoxicity. This interaction is absent in human cells due to differences in three amino acids at the boundary of the FAS extracellular and transmembrane domains.\",\n      \"method\": \"Mass spectrometry interactome, co-immunoprecipitation, FAS surface expression by flow cytometry, CMTM6 deletion, FAS ligand cytotoxicity assays, human-mouse domain comparison and mutagenesis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MS identification plus Co-IP plus functional FAS ligand assays plus domain-level mechanistic explanation, single lab with multiple methods\",\n      \"pmids\": [\"41634378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In ANCA-associated vasculitis (AAV), monocytes have reduced CMTM6 expression, leading to enhanced lysosomal degradation of PD-L1, lower PD-L1 surface expression, and increased T-cell stimulatory capacity. Inhibiting lysosomal function corrected this phenotype by increasing PD-L1.\",\n      \"method\": \"In vitro co-culture of patient monocytes, surface PD-L1 measurement, lysosomal inhibitor experiments, CD4+ T-cell activation/proliferation assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — patient monocyte co-cultures plus pharmacological rescue of lysosomal pathway, mechanistic link established, single lab\",\n      \"pmids\": [\"34108971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAVS co-localizes with and stabilizes CMTM6, shielding it from lysosomal degradation. Disruption of the MAVS-CMTM6 axis provokes mitochondrial dysfunction and ROS accumulation, leading to senescence and a SASP marked by CCL3, which recruits CD8+ T cells for antitumor immunity in renal carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, co-localization imaging, MAVS-deficient mouse models, ROS scavenging (NAC), CD8+ T-cell depletion, flow cytometry, PD-1 blockade combination\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mass spectrometry plus in vivo MAVS-KO models plus pharmacological rescue, single lab\",\n      \"pmids\": [\"41469142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CMTM6 inhibits ocular surface inflammation and maintains corneal epithelial barrier function via suppression of the NF-κB p65 signaling pathway. CMTM6 knockout mice showed more severe dry eye disease, barrier disruption, and reduced ZO-1 expression. NF-κB p65 inhibition reversed the excessive inflammation caused by CMTM6 knockdown.\",\n      \"method\": \"Cmtm6 knockout mice, siRNA/shRNA knockdown, lentiviral overexpression, NF-κB p65 inhibitor (JSH-23), ECIS barrier assay, immunofluorescence (ZO-1), flow cytometry, cytometric bead array\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model plus pharmacological NF-κB rescue plus multiple barrier function readouts, single lab\",\n      \"pmids\": [\"38165704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CMTM6 interacts with Nectin-2 (PVRL2) via RAB14/RAB11-mediated endosomal trafficking, inhibiting Nectin-2 degradation through both lysosomal and proteasomal pathways. CMTM6 knockdown enhances NK cell infiltration into gastric tumors and suppresses tumor growth.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, cycloheximide chase assay, lysosomal/proteasomal inhibitors, animal models of gastric cancer, tumor tissue microarray\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP plus CHX chase plus pharmacological degradation pathway dissection plus in vivo model, single lab\",\n      \"pmids\": [\"41840509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CMTM6 maintains TAK1 stability by inhibiting its ubiquitin-proteasome degradation in fibroblast-like synoviocytes (FLSs), thereby activating the TNF/TNFR pathway and downstream NF-κB/MAPK signaling and promoting synovial inflammation in rheumatoid arthritis. AAV-mediated Cmtm6 knockdown attenuated arthritis severity in collagen-induced arthritis mice.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, ubiquitination assay, cycloheximide (CHX) assay, RNA-sequencing, AAV-shCmtm6 treatment in CIA mice, micro-CT and histology\",\n      \"journal\": \"Journal of orthopaedic translation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination/CHX assays plus in vivo CIA model, single lab with multiple methods\",\n      \"pmids\": [\"41836582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CMTM6 knockdown in HNSCC cells reduced nuclear β-catenin expression, inhibited stem cell-like properties, TGFβ-induced EMT, and cell proliferation. CMTM6 silencing also decreased PD-L1, delayed tumor growth in vivo, and increased CD8+ and CD4+ T-cell infiltration while reducing exhausted T-cell populations.\",\n      \"method\": \"shRNA knockdown, western blotting, flow cytometry, T-cell infiltration analysis in syngeneic SCC7 tumor model\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — shRNA KD with multiple cellular and in vivo readouts, single lab\",\n      \"pmids\": [\"31771985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CMTM6 and CMTM7 are co-induced with EMT (driven by SNAI1) in breast cancer cells and together regulate surface PD-L1 expression. Dual knockdown of CMTM6 and CMTM7 significantly decreased PD-L1 surface expression more than either alone in mesenchymal breast cancer cells.\",\n      \"method\": \"SNAI1-inducible EMT model in MCF-7 cells, siRNA knockdown of CMTM6 and/or CMTM7, flow cytometry for surface PD-L1\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — dual siRNA knockdown plus inducible EMT model, single lab\",\n      \"pmids\": [\"33803139\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CMTM6 is a ubiquitously expressed type-3 transmembrane protein that acts as a broad stabilizer of multiple cell-surface proteins—most notably PD-L1, but also CD58, EGFR, HER2, Glut1, Nectin-2, vimentin, p21, TAK1, β-catenin, ENO-1, and (in mice) FAS—by co-localizing with them in recycling endosomes and preventing their ubiquitin-mediated lysosomal or proteasomal degradation, thereby controlling immune checkpoint signaling, receptor trafficking, metabolic reprogramming, cytoskeletal dynamics, and cell-cycle progression; it is also stabilized by binding partners such as MAVS and FLT3 via transmembrane domain interactions, and its expression is post-transcriptionally regulated by HuR binding to AU-rich elements in its 3'UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CMTM6 is a transmembrane protein that functions as a broad post-translational stabilizer of cell-surface and signaling proteins by binding them in recycling endosomes and diverting them from ubiquitin-mediated degradation, with central roles in immune checkpoint control, receptor trafficking, and tumor biology [#0, #1]. Its founding and best-defined function is stabilization of PD-L1: CMTM6 (and its closest family member CMTM4) associates with PD-L1 at the plasma membrane and in recycling endosomes, reduces PD-L1 ubiquitination, extends its half-life without altering CD274 transcription, and thereby sustains tumor-cell suppression of T cells [#0, #1]. CMTM6 acts as a shared, rate-limiting chaperone for which client proteins compete: CD58 and PD-L1 compete for CMTM6 binding, so loss of one client frees CMTM6 to stabilize the other [#2]. Structurally, CMTM6 forms a membrane-bound complex with full-length PD-L1 that enhances PD-1 binding and delays PD-1/PD-L1 dissociation, and a CMTM6-targeting nanobody relieves T-cell immunosuppression and inhibits tumor growth in a CD8+ T-cell-dependent manner [#16]. Beyond PD-L1, CMTM6 stabilizes a wide range of clients by the same endosomal anti-degradation logic\\u2014EGFR via RAB11-positive recycling endosomes [#11], Glut1 in a Rab11-dependent complex to support glycolysis and metastasis [#13], Nectin-2/PVRL2 via RAB14/RAB11 trafficking to restrain NK-cell attack [#22], \\u03b2-catenin [#12], the cell-cycle inhibitor p21 [#3], vimentin [#4], and TAK1 [#23]\\u2014linking it to receptor signaling, metabolic reprogramming, epithelial-mesenchymal transition, and inflammatory pathways. CMTM6 itself is regulated post-transcriptionally and by partner binding: HuR stabilizes CMTM6 mRNA through AU-rich elements in its 3'UTR [#10], while MAVS [#20] and the receptor tyrosine kinase FLT3, via a transmembrane-domain interaction, shield CMTM6 protein from degradation [#17]. Loss of CMTM6 can trigger DNA damage response, senescence, and a SASP that recruits T cells [#14, #20]. CMTM6 also has non-tumor physiological roles, including maintaining adaxonal Schwann cell membrane structure and constraining axonal diameter [#7], suppressing ocular surface inflammation via NF-\\u03baB p65 [#21], and, in mice but not humans, negatively regulating surface FAS to limit FAS-ligand cytotoxicity [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established the founding function of CMTM6 by answering how PD-L1 protein is maintained at the cell surface independent of transcription, identifying CMTM6 as the rate-limiting stabilizer of the immune checkpoint.\",\n      \"evidence\": \"Genome-wide CRISPR and haploid genetic screens, Co-IP, ubiquitination and half-life assays, quantitative membrane proteomics, and T-cell suppression assays in two independent studies\",\n      \"pmids\": [\"28813417\", \"28813410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the E3 ligase machinery from which CMTM6 protects PD-L1\", \"Mechanism of the CMTM6-PD-L1 transmembrane interaction not structurally defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a physiological, non-immune role for CMTM6 by localizing it to the adaxonal Schwann cell membrane and showing it constrains axonal diameter, demonstrating function beyond checkpoint biology.\",\n      \"evidence\": \"Label-free proteomics, STED and cryo-immuno EM, and Schwann cell-specific conditional knockout mice with electrophysiology\",\n      \"pmids\": [\"32908139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular client mediating axonal diameter control not identified\", \"Connection to the endosomal stabilization mechanism not established in this tissue\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended CMTM6 into the tumor microenvironment as a transferable factor, showing exosomal CMTM6 polarizes macrophages and that CMTM6 promotes OSCC via NRP1 interaction.\",\n      \"evidence\": \"Exosome isolation with macrophage co-culture and 4NQO mouse model; Co-IP and gain/loss-of-function invasion assays\",\n      \"pmids\": [\"33104837\", \"32642284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NRP1-dependent CMTM6 degradation mechanism not dissected\", \"Exosomal ERK1/2 activation mechanism downstream of CMTM6 unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized the stabilization mechanism beyond surface receptors by showing CMTM6 protects intracellular and cytoskeletal clients (p21, vimentin, ENO-1) from degradation, linking it to cell-cycle, EMT, and metabolic/Wnt signaling.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, cell cycle analysis, proteomics, and xenograft models across HCC and OSCC\",\n      \"pmids\": [\"35304440\", \"33757532\", \"33434185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these are direct binding clients or indirect effects not fully separated\", \"Specificity determinants for the diverse client set unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified upstream regulation of CMTM6 itself, answering how its abundance is set, via HuR-mediated mRNA stabilization and EMT/SNAI1-driven co-induction with CMTM7.\",\n      \"evidence\": \"RNA-IP, mRNA stability assays, HuR inhibitor, and SNAI1-inducible EMT model with dual siRNA knockdown\",\n      \"pmids\": [\"33649535\", \"33803139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of transcriptional vs post-transcriptional control across tissues unknown\", \"Functional redundancy boundary between CMTM6 and CMTM7 not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided structural and biochemical mechanism by reconstituting the membrane CMTM6-PD-L1 complex and showing CMTM6 directly enhances PD-1/PD-L1 affinity, and demonstrated loss-of-CMTM6 triggers DDR-driven senescence.\",\n      \"evidence\": \"In vitro reconstitution with binding kinetics and anti-CMTM6 nanobody in CT26 mice; CMTM6 depletion with DNA damage and micronucleus assays in ccRCC\",\n      \"pmids\": [\"36418428\", \"35024247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the complex not determined\", \"Mechanism linking CMTM6 loss to DNA damage response not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined CMTM6 as a shared limiting chaperone subject to client competition, and extended its trafficking-based stabilization to EGFR and \\u03b2-catenin with therapeutic targeting.\",\n      \"evidence\": \"CRISPR screen, proteomics, humanized mouse and PDX models; Co-IP, RAB11 co-localization imaging, ubiquitination assays, and CMTM6-targeting nanobody\",\n      \"pmids\": [\"37327789\", \"40521789\", \"38101607\", \"31771985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy of client affinities not quantified\", \"How a single protein selects among competing clients spatially unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened the trafficking mechanism to a metabolic transporter and to transcription/epigenetic feedback, with Glut1 stabilization via a Rab11 complex and an EP300-CMTM6-IGF2BP1 loop.\",\n      \"evidence\": \"Endosomal fractionation, Co-IP, glycolysis assays, metastasis models; ChIP-seq, ubiquitination assay, RIP, and PDX models\",\n      \"pmids\": [\"39218981\", \"39488785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffold role of CMTM6 within the Rab11 transport complex unclear\", \"Whether IGF2BP1 stabilization is direct binding not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established CMTM6 as a homeostatic anti-inflammatory factor at epithelial barriers, showing it suppresses NF-\\u03baB p65 to maintain corneal epithelial integrity.\",\n      \"evidence\": \"Cmtm6 knockout mice, NF-\\u03baB inhibitor rescue, barrier (ECIS) and ZO-1 immunofluorescence assays\",\n      \"pmids\": [\"38165704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular client linking CMTM6 to NF-\\u03baB suppression not identified\", \"Whether this involves the endosomal stabilization mechanism unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified partners that stabilize CMTM6 protein itself, with MAVS shielding CMTM6 from lysosomal degradation and the MAVS-CMTM6 axis governing mitochondrial stress and antitumor immunity.\",\n      \"evidence\": \"Co-IP, mass spectrometry, MAVS-deficient mouse models, ROS scavenging, and CD8+ T-cell depletion\",\n      \"pmids\": [\"41469142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Subcellular site of MAVS-CMTM6 interaction not pinned down\", \"How CMTM6 loss provokes mitochondrial dysfunction mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined transmembrane-domain-mediated partner control and species-specific clients, with FLT3 stabilizing CMTM6 in AML, CMTM6 stabilizing Nectin-2 and TAK1, and a mouse-specific FAS interaction.\",\n      \"evidence\": \"Transmembrane-domain Co-IP, allogeneic HCT and CIA mouse models, CHX chase, mass spectrometry interactome, and human-mouse domain mutagenesis\",\n      \"pmids\": [\"41043134\", \"41840509\", \"41836582\", \"41634378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of transmembrane-domain recognition across partners not resolved\", \"General rules predicting which receptors CMTM6 stabilizes vs which stabilize CMTM6 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what structural and biochemical features determine CMTM6 client selectivity and the directionality of stabilization, and which ubiquitin ligases CMTM6 antagonizes for each client.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unifying structural model of CMTM6 client recognition\", \"Cognate E3 ligases for most clients unidentified\", \"Quantitative client-competition hierarchy not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 16]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 1, 11, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 11, 13, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 16]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [11, 13, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 12, 23]}\n    ],\n    \"complexes\": [\n      \"CMTM6-PD-L1 complex\",\n      \"CMTM6-Glut1-Rab11 complex\"\n    ],\n    \"partners\": [\n      \"CD274\",\n      \"CD58\",\n      \"EGFR\",\n      \"SLC2A1\",\n      \"PVRL2\",\n      \"CTNNB1\",\n      \"FLT3\",\n      \"MAVS\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}