Affinage

TM9SF3

Transmembrane 9 superfamily member 3 · UniProt Q9HD45

Length
589 aa
Mass
67.9 kDa
Annotated
2026-06-10
12 papers in source corpus 5 papers cited in narrative 3 extracted findings
Cross-family judge faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TM9SF3 is a Golgi-resident transmembrane protein that functions as a selective autophagy receptor (Golgiphagy receptor) directing Golgi fragments to autophagosomes for lysosomal degradation under nutrient stress and Golgi-stress conditions (PMID:40609542, PMID:41187704, PMID:40709739). It engages the autophagy machinery by binding all six mammalian ATG8 proteins through N-terminal LC3-interacting regions (LIRs), and loss of TM9SF3 blocks nutrient-stress-induced Golgi fragmentation and reduces targeting of Golgi fragments to autophagosomes; through this activity it maintains Golgi integrity and glycosylation fidelity, with LIR mutations compromising protein glycosylation and overexpression promoting degradation of incompletely glycosylated proteins (PMID:40609542, PMID:41187704, PMID:40709739). In a distinct role, TM9SF3 mediates translocation (flop) of PIP2 from the inner to the outer plasma membrane leaflet in response to extracellular acidification, supporting PIP2-dependent cytoskeletal organization and collective cell migration during zebrafish gastrulation (PMID:41053185). In Jurkat T-cell leukemia cells TM9SF3 positively regulates proliferation and invasion and is a direct target of miR-1193 (PMID:28390114).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2017 Medium

    Established a first functional and regulatory handle on TM9SF3 by placing it downstream of a microRNA and linking it to cancer cell behavior, before any molecular mechanism was known.

    Evidence Luciferase reporter assay plus overexpression/knockdown with proliferation and invasion assays in Jurkat leukemia cells

    PMID:28390114

    Open questions at the time
    • No molecular mechanism connecting TM9SF3 to proliferation or invasion
    • Single cell line and single lab, no in vivo validation
    • Does not address subcellular localization or biochemical activity
  2. 2025 High

    Defined TM9SF3 as a Golgiphagy receptor, answering how Golgi fragments are selectively delivered to autophagosomes and linking this clearance to glycosylation quality control.

    Evidence TM9SF3 knockout, LIR mutant and overexpression analyses, ATG8-binding assays, autophagosome targeting and Golgi protein degradation assays in U2OS cells

    PMID:40609542 PMID:40709739 PMID:41187704

    Open questions at the time
    • Structural basis of LIR–ATG8 engagement not resolved
    • How Golgi stress signals are sensed and coupled to TM9SF3 activation is unknown
    • Relationship between Golgiphagy role and the plasma-membrane PIP2 role is unclear
  3. 2025 High

    Identified a separate plasma-membrane function for TM9SF3 in pH-triggered PIP2 transbilayer movement, connecting it to cytoskeletal reorganization and collective cell migration in vivo.

    Evidence Genome-wide screen, live-cell PIP2 topology imaging, and zebrafish Tm9sf3 mutant migration/cytoskeletal assays

    PMID:41053185

    Open questions at the time
    • Whether TM9SF3 itself is the PIP2 transporter or a regulator is not distinguished
    • Mechanism by which extracellular acidification activates the flop is unknown
    • Localization at the plasma membrane vs Golgi for this function not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TM9SF3's Golgi-based Golgiphagy receptor activity and its plasma-membrane PIP2 translocation activity are mechanistically and topologically reconciled remains unresolved.
  • No structural model of TM9SF3 or its lipid/ATG8 binding sites
  • No biochemical demonstration of intrinsic transport activity
  • Unclear whether the two functions occur in the same or distinct cellular pools

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 1 GO:0008289 lipid binding 1 GO:0038024 cargo receptor activity 1
Localization
GO:0005794 Golgi apparatus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-9612973 Autophagy 1

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2025 TM9SF3 is a Golgi-resident transmembrane protein that acts as a selective autophagy receptor (Golgiphagy receptor) essential for lysosomal degradation of Golgi fragments under nutrient stress and multiple Golgi-stress conditions (monensin, brefeldin A, intra-Golgi glycosylation disruption). TM9SF3 binds all six mammalian ATG8 proteins through N-terminal LC3-interacting regions (LIRs). Knockout of TM9SF3 blocks nutrient-stress-induced Golgi fragmentation and reduces targeting of Golgi fragments to autophagosomes, resulting in decreased Golgi protein degradation. Mutations in TM9SF3 LIRs compromise protein glycosylation, while TM9SF3 overexpression promotes degradation of incompletely glycosylated proteins. TM9SF3 knockout in U2OS cells, LIR mutant analysis, overexpression experiments, autophagosome targeting assays, Golgi protein degradation assays, ATG8-binding assays Developmental cell High 40609542 40709739 41187704
2025 TM9SF3 mediates phosphatidylinositol 4,5-bisphosphate (PIP2) translocation (flop) from the inner to the outer leaflet of the plasma membrane in response to extracellular acidification. Genome-wide screening identified TM9SF3 as a critical regulator of this PIP2 translocation. In zebrafish, mutant anterior axial mesoderm lacking Tm9sf3 exhibits disorganized collective cell migration due to impaired PIP2-dependent cytoskeletal organization during gastrulation. Genome-wide screening, zebrafish Tm9sf3 mutant analysis, live-cell imaging of PIP2 topology, collective cell migration assays, cytoskeletal organization assays Nature communications High 41053185
2017 TM9SF3 is a direct target of miR-1193, as confirmed by luciferase reporter gene assay. TM9SF3 positively regulates cell proliferation and invasion in Jurkat human T-cell leukemia cells, as demonstrated by overexpression and knockdown experiments. Luciferase reporter gene assay, gene overexpression and knockdown in Jurkat cells, proliferation and invasion assays Oncology research Medium 28390114

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 miR-1193 Suppresses the Proliferation and Invasion of Human T-Cell Leukemia Cells Through Directly Targeting the Transmembrane 9 Superfamily 3 (TM9SF3). Oncology research 21 28390114
2020 Expression and purification of the antimicrobial peptide Bin1b in Escherichia coli tagged with the fusion proteins CusF3H+ and SmbP. Protein expression and purification 15 33129981
2019 Optimizing Periplasmic Expression in Escherichia coli for the Production of Recombinant Proteins Tagged with the Small Metal-Binding Protein SmbP. Molecular biotechnology 13 30997666
2025 TM9SF3 is a Golgi-resident ATG8-binding protein essential for Golgi-selective autophagy. Developmental cell 11 40609542
2021 The Small Metal-Binding Protein SmbP Simplifies the Recombinant Expression and Purification of the Antimicrobial Peptide LL-37. Antibiotics (Basel, Switzerland) 9 34680851
2024 High-Yield Expression and Purification of Scygonadin, an Antimicrobial Peptide, Using the Small Metal-Binding Protein SmbP. Microorganisms 6 38399682
2025 TM9SF3 is a mammalian Golgiphagy receptor that safeguards Golgi integrity and glycosylation fidelity. Autophagy 4 40709739
2021 Expression and Purification of the VpDef Defensin in Escherichia coli using the Small Metal-Binding Proteins CusF3H+ and SmbP. Protein and peptide letters 4 32520670
2021 Expression and Purification of Recombinant Proteins in Escherichia coli Tagged with the Metal-Binding Proteins SmbP and CusF3H. Methods in molecular biology (Clifton, N.J.) 4 33128759
2025 Golgiphagy mediated by TM9SF3 acts as quality control for stressed Golgi. Developmental cell 1 41187704
2022 The Small Metal-Binding Protein SmbP Improves the Expression and Purification of the Recombinant Antitumor-Analgesic Peptide from the Chinese Scorpion Buthus martensii Karsch in Escherichia coli. Current issues in molecular biology 1 35723324
2025 Cells adapt to extracellular acidic pH through TM9SF3-mediated PI(4,5)P2 flop. Nature communications 0 41053185

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