Affinage

TMED9

Transmembrane emp24 domain-containing protein 9 · UniProt Q9BVK6

Length
235 aa
Mass
27.3 kDa
Annotated
2026-06-10
14 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMED9 is a p24-family cargo receptor of the early secretory pathway that selectively entraps misfolded protein cargos and couples ER-Golgi membrane dynamics to quality control (PMID:31348885, PMID:39303030). Cryo-EM shows that TMED9 self-oligomerizes into octamers, dodecamers, and higher-order assemblies driven by a symmetry mismatch between its trimeric coiled-coil and tetrameric transmembrane domains; this oligomerization favors recruitment of COPI (but not COPII) coatomers to drive retrograde transport, while the luminal Golgi-dynamics domain directly engages frameshifted MUC1 cargo to explain cargo entrapment (PMID:39303030). The same receptor functions in the RESET pathway for misfolded GPI-anchored proteins, associating specifically with misfolded (but not wild-type) GPI-APs after their release from calnexin and conveying them from the ER to the Golgi (PMID:40203033). The small molecule BRD4780 binds TMED9 directly, releases trapped misfolded MUC1-fs cargo, and reroutes it for lysosomal degradation, with TMED9 deletion phenocopying this effect; acute BRD4780 treatment shifts TMED9 from ER to Golgi to block RESET (PMID:31348885, PMID:40203033). Independently of cargo capture, TMED9 interacts with SEC12 at the ERGIC to establish ERGIC-ERES membrane contacts that transactivate COPII assembly on the ERGIC and support stress-induced autophagosome biogenesis, a function also engaged downstream of PTK2/FAK inhibition (PMID:34561617, PMID:42144738). TMED9 is transcriptionally induced by the IRE1-XBP1s arm of the unfolded protein response and selectively stabilizes ATF6 by preventing its ubiquitin-dependent proteasomal degradation, linking the receptor to ER stress adaptation and survival (PMID:42062868). In cancer, TMED9 acts downstream of TMED3 to promote pro-metastatic TGFα biogenesis and secretion and cell migration (PMID:31253868).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2019 High

    Established TMED9 as a cargo receptor that entraps misfolded proteins in the early secretory pathway and as the direct target of a small-molecule that rescues this entrapment.

    Evidence Direct small-molecule binding (BRD4780), genetic deletion/knockdown phenocopy, and protein-clearance readouts across patient cells, knockin mouse kidneys, and patient kidney organoids

    PMID:31348885

    Open questions at the time
    • Structural basis of misfolded-cargo recognition not defined at this stage
    • Whether entrapment is specific to MUC1-fs or general to misfolded cargos unresolved here
  2. 2021 High

    Revealed a cargo-independent role: TMED9 binds SEC12 at the ERGIC to nucleate ERGIC-ERES membrane contacts and COPII assembly required for stress-induced autophagosome biogenesis.

    Evidence Reciprocal Co-IP, super-resolution and electron microscopy of membrane contacts, siRNA knockdown with COPII assembly and autophagy flux assays

    PMID:34561617

    Open questions at the time
    • Molecular determinants on TMED9 mediating SEC12 binding not mapped
    • Relationship between this COPII-promoting role and the COPI-favoring oligomeric state unresolved
  3. 2024 High

    Provided the structural mechanism for cargo entrapment: TMED9 self-oligomerizes via a coiled-coil/transmembrane symmetry mismatch, biasing coat recruitment toward COPI retrograde transport.

    Evidence Cryo-EM structure determination, domain mutagenesis, and COPI/COPII recruitment assays with luminal-domain cargo interaction

    PMID:39303030

    Open questions at the time
    • How oligomeric state is regulated in cells not established
    • Reconciliation with TMED9's COPII-promoting ERGIC role not addressed
  4. 2025 High

    Extended TMED9's quality-control function to misfolded GPI-anchored proteins, showing selective recognition downstream of calnexin and BRD4780-dependent localization control.

    Evidence Biochemical fractionation, Co-IP, live-cell imaging, siRNA depletion, and BRD4780 treatment with ER-export readouts

    PMID:40203033

    Open questions at the time
    • Structural basis for misfolded-vs-WT GPI-AP discrimination unknown
    • How BRD4780 shifts TMED9 from ER to Golgi mechanistically unresolved
  5. 2026 Medium

    Connected TMED9 to ER-stress signaling, showing it is an IRE1-XBP1s transcriptional target that in turn stabilizes ATF6 against proteasomal degradation.

    Evidence Luciferase reporter, qRT-PCR, CRISPR/siRNA loss-of-function, pulse-chase, ubiquitination/degradation and apoptosis assays

    PMID:42062868

    Open questions at the time
    • Direct biochemical mechanism by which TMED9 protects ATF6 from ubiquitination not defined
    • No independent replication yet
  6. 2026 Medium

    Linked TMED9-driven ERGIC-ERES contacts to a druggable non-classical autophagy axis activated by PTK2/FAK inhibition in PDAC.

    Evidence Kinase-inhibitor screen, ERES live-cell imaging, Co-IP, and in vitro/in vivo PDAC viability assays implicating AKAP13

    PMID:42144738

    Open questions at the time
    • Direct molecular link between AKAP13 dephosphorylation and TMED9 function unclear
    • No independent replication yet

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TMED9's distinct activities — COPI-favoring oligomerization for cargo entrapment versus SEC12-dependent COPII promotion and ATF6 stabilization — are coordinated or switched within a single cell remains unresolved.
  • No unifying model integrating retrograde entrapment and forward/COPII-promoting roles
  • Regulation of TMED9 oligomeric state in vivo unknown
  • Cargo-selectivity code for misfolded proteins not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 3 GO:0060089 molecular transducer activity 1
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005794 Golgi apparatus 2 GO:0031410 cytoplasmic vesicle 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2 R-HSA-8953897 Cellular responses to stimuli 1
Partners
AKAP13ATF6BPIFB3CNIH4SEC12TMED3

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 BRD4780 binds TMED9 directly, releasing trapped misfolded MUC1-fs cargo from TMED9-containing vesicles of the early secretory pathway and re-routing it for lysosomal degradation; TMED9 deletion phenocopies this effect, establishing TMED9 as a cargo receptor that entraps misfolded proteins in the early secretory pathway. Small molecule binding assay, patient cell lines, knockin mouse kidneys, patient kidney organoids, TMED9 deletion/knockdown with protein clearance readouts Cell High 31348885
2024 Cryo-EM structures reveal that TMED9 self-oligomerizes into octamers, dodecamers, and higher-order oligomers driven by an intrinsic symmetry mismatch between its trimeric coiled-coil domain and tetrameric transmembrane domain. The luminal Golgi-dynamics domain directly interacts with frameshifted MUC1 cargo. TMED9 oligomerization favors recruitment of COPI (but not COPII) coatomers, facilitating retrograde transport and explaining cargo entrapment. Cryo-electron microscopy structure determination, domain mutagenesis, COPI/COPII recruitment assays Science advances High 39303030
2021 TMED9 interacts with SEC12 at the ER-Golgi intermediate compartment (ERGIC) to establish a new ERGIC-ERES membrane contact (2–5 nm distance) that transactivates COPII assembly on the ERGIC, promotes formation of ERGIC-derived COPII vesicles, and is required for stress-induced autophagosome biogenesis. Co-immunoprecipitation, super-resolution and electron microscopy, siRNA knockdown, COPII assembly assays, autophagy flux assays Cell research High 34561617
2025 TMED9 plays a requisite role in the RESET pathway for quality control of misfolded GPI-anchored proteins (GPI-APs): it associates with misfolded GPI-APs (but not wild-type GPI-APs) in the ER after their release from calnexin, and conveys them to the Golgi. siRNA depletion or BRD4780 treatment blocks ER-export of misfolded GPI-APs specifically. Acute BRD4780 treatment shifts TMED9 localization from ER to Golgi cisternae, blocking RESET; removal of BRD4780 restores ER localization and RESET activity. Biochemical fractionation, co-immunoprecipitation, live-cell imaging, siRNA knockdown, chemical inhibitor (BRD4780) treatment, localization assays PLoS biology High 40203033
2019 TMED9 acts downstream of TMED3 in colon cancer cells and promotes pro-metastatic behavior via regulation of TGFα biogenesis and secretion; TMED9 knockdown compromises TGFα biogenesis and impairs cell migration. TMED9 function is linked to CNIH4 (a TGFα exporter) and establishes a positive feedback loop with TGFα and GLI1 that opposes TMED3-WNT-TCF signaling. siRNA knockdown, functional rescue assays, migration/invasion assays, gene expression analysis across three colon cancer cell lines Oncogene Medium 31253868
2015 p24α2 (TMED9) is localized to pre-synaptic terminals in the mammalian brain and is condensed at active zone-docked synaptic vesicles, as established by immunohistochemistry, subcellular fractionation, and synaptic vesicle immunoisolation. Amyloid precursor protein and γ-secretase components co-localize at the same active zone-docked synaptic vesicles. Immunohistochemistry, subcellular fractionation, synaptic vesicle immunoisolation Journal of neurochemistry Medium 25438880
2021 TMED9 interacts with BPIFB3 (identified by proximity-dependent biotinylation/BioID followed by mass spectrometry) and regulates non-canonical autophagy and the replication of enteroviruses and flaviviruses. BioID proximity labeling, mass spectrometry, siRNA knockdown, viral replication assays Journal of cell science Medium 33277377
2026 Under ER stress, TMED9 expression is transcriptionally induced by the IRE1-XBP1s pathway via a conserved UPRE-like element in its promoter. TMED9 selectively stabilizes ATF6 by preventing its ubiquitin-dependent proteasomal degradation, without affecting IRE1 or PERK signaling. TMED9 loss impairs ATF6 activation and increases sensitivity to ER stress-induced apoptosis. qRT-PCR, luciferase reporter assay, western blotting, CRISPR-Cas9 knockout, siRNA knockdown, RNA-seq, pulse-chase, ubiquitination and degradation assays, cell viability/apoptosis assays Cellular & molecular biology letters Medium 42062868
2026 PTK2/FAK inhibition triggers TMED9-mediated autophagy via enhanced ERGIC-ERES membrane contact. This non-classical autophagic flux is sensitive to TMED9 expression levels and is associated with spatial redistribution of ER exit sites (ERES). AKAP13 is a FAKi-responsive protein that undergoes dephosphorylation upon FAK inhibition and contributes to TMED9-mediated ERES-associated autophagy. High-content kinase inhibitor library screening, siRNA knockdown, live-cell imaging of ERES, co-immunoprecipitation (TMED9-ERGIC interactions), in vitro and in vivo PDAC cell viability assays Autophagy Medium 42144738

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy. Cell 160 31348885
2021 A new type of ERGIC-ERES membrane contact mediated by TMED9 and SEC12 is required for autophagosome biogenesis. Cell research 69 34561617
2019 The protein secretion modulator TMED9 drives CNIH4/TGFα/GLI signaling opposing TMED3-WNT-TCF to promote colon cancer metastases. Oncogene 49 31253868
2011 MicroRNAs 296 and 298 are imprinted and part of the GNAS/Gnas cluster and miR-296 targets IKBKE and Tmed9. RNA (New York, N.Y.) 40 22114321
2023 The many hats of transmembrane emp24 domain protein TMED9 in secretory pathway homeostasis. Frontiers in cell and developmental biology 19 36733337
2021 Proteomics-based identification of TMED9 is linked to vascular invasion and poor prognoses in patients with hepatocellular carcinoma. Journal of biomedical science 17 33888099
2021 BPIFB3 interacts with ARFGAP1 and TMED9 to regulate non-canonical autophagy and RNA virus infection. Journal of cell science 10 33277377
2024 Molecular basis of TMED9 oligomerization and entrapment of misfolded protein cargo in the early secretory pathway. Science advances 8 39303030
2015 Pre-synaptic localization of the γ-secretase-inhibiting protein p24α2 in the mammalian brain. Journal of neurochemistry 8 25438880
2025 TMED9 coordinates the clearance of misfolded GPI-anchored proteins out of the ER and into the Golgi. PLoS biology 3 40203033
2025 TMED9 coordinates the clearance of misfolded GPI-anchored proteins out of the endoplasmic reticulum and into the Golgi. bioRxiv : the preprint server for biology 1 39974996
2025 Targeting the Cargo Receptor TMED9 as a Therapeutic Strategy Against Brain Tumors. Cells 1 40497947
2026 IRE1-XBP1driven induction of TMED9 stabilizes ATF6 during ER stress to promote cell survival. Cellular & molecular biology letters 0 42062868
2026 PTK2/FAK inhibition triggers TMED9-mediated protective autophagy in pancreatic cancer cell via enhancing ERGIC-ERES contact. Autophagy 0 42144738

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