Affinage

TMEM39A

Transmembrane protein 39A · UniProt Q9NV64

Length
488 aa
Mass
55.7 kDa
Annotated
2026-06-10
10 papers in source corpus 3 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM39A/SUSR2 is an ER-localized transmembrane protein that coordinates COPII-dependent membrane trafficking to control phosphoinositide homeostasis, autophagy, and bulk secretion (PMID:31806350, PMID:39521045). It functions as a COPII adaptor that promotes ER-to-Golgi transport of the PtdIns(4)P phosphatase SAC1 by simultaneously binding SAC1 and the COPII subunits SEC23/SEC24; loss of TMEM39A retains SAC1 on the ER, elevating VPS34-generated PtdIns(3)P to drive autophagosome formation while raising late endosomal/lysosomal PtdIns(4)P that recruits the HOPS complex, promotes SNARE assembly, and enhances lysosomal degradative capacity during autophagosome maturation (PMID:31806350). Through interaction with the dynein intermediate chain DYNC1I2, TMEM39A maintains perinuclear lysosome positioning, and its loss disperses lysosomes to the cell periphery and impairs mTOR signaling with consequent activation of the TFEB-like factor HLH-30 (PMID:33531362). TMEM39A also co-localizes with the COPII coat in large vesicles and cooperates with TMEM131 to enable bulk secretion of extracellular matrix proteins including collagens (PMID:39521045).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2019 High

    Established TMEM39A as an ER COPII adaptor that links phosphoinositide metabolism to autophagy by escorting the phosphatase SAC1 out of the ER, answering how SAC1 reaches its site of action and how its mislocalization reshapes the lipid landscape.

    Evidence Reciprocal Co-IP with SAC1 and SEC23/SEC24, subcellular fractionation, and knockdown with phosphoinositide and autophagy-flux readouts in mammalian cells

    PMID:31806350

    Open questions at the time
    • Structural basis of simultaneous SAC1 and SEC23/SEC24 binding not resolved
    • Whether TMEM39A is itself a COPII cargo or a coat-recruitment factor not distinguished
    • Stoichiometry and dynamics of adaptor-cargo assembly unknown
  2. 2019 High

    Demonstrated that TMEM39A loss couples elevated PtdIns(3)P (autophagosome formation) and elevated lysosomal PtdIns(4)P (HOPS recruitment, SNARE assembly, degradation) into a coordinated regulation of both autophagosome initiation and maturation.

    Evidence TMEM39A knockdown with lipid measurements, HOPS recruitment, SNARE assembly, and lysosomal activity assays

    PMID:31806350

    Open questions at the time
    • Direct enzymatic link between SAC1 retention and lysosomal PtdIns(4)P increase not fully mapped
    • Physiological contexts where TMEM39A tunes autophagy not defined
  3. 2021 Medium

    Connected TMEM39A to lysosome positioning and nutrient signaling by identifying a dynein-intermediate-chain interaction, showing the protein has roles beyond ER trafficking.

    Evidence Co-IP of TMEM39A-DYNC1I2 and loss-of-function in C. elegans tmem-39 mutants and mammalian cells with lysosome localization, mTOR, and HLH-30/TFEB readouts; live imaging of lysosome morphology

    PMID:33531362

    Open questions at the time
    • Single lab; DYNC1I2 interaction not reciprocally validated across systems
    • Mechanism linking lysosome dispersal to mTOR suppression unresolved
    • Whether positioning defect is a direct dynein-tethering role or a downstream consequence unclear
  4. 2024 Medium

    Extended TMEM39A function to bulk cargo export by showing it partners with TMEM131 in large COPII vesicles to secrete extracellular matrix proteins, broadening its trafficking role from a single phosphatase to oversized secretory cargo.

    Evidence TMEM39A-FLAG IP-proteomics identifying TMEM131, TMEM131 knockdown with collagen secretion readout, and co-localization imaging in C. elegans and human sarcoma cells

    PMID:39521045

    Open questions at the time
    • Single lab; direct TMEM39A-TMEM131 binding interface not characterized
    • How large COPII vesicle formation is mechanistically driven not established
    • Relationship between the SAC1/autophagy role and the bulk-secretion role unintegrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TMEM39A's distinct activities — SAC1 escort, dynein-dependent lysosome positioning, and TMEM131-dependent bulk secretion — are integrated or differentially regulated within a single protein remains unresolved.
  • No structural model of TMEM39A
  • Domain assignments for its multiple interactions not defined
  • No mammalian disease or physiological phenotype directly linked in the available corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005783 endoplasmic reticulum 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9612973 Autophagy 2
Partners
DYNC1I2SAC1SEC23SEC24TMEM131

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 TMEM39A/SUSR2 is an ER-localized transmembrane protein that acts as an adaptor protein promoting ER-to-Golgi transport of the PtdIns(4)P phosphatase SAC1 by interacting with both SAC1 and the COPII subunits SEC23/SEC24. Co-immunoprecipitation, knockdown experiments, subcellular fractionation/localization Molecular cell High 31806350
2019 Depletion of TMEM39A/SUSR2 retains SAC1 on the ER, leading to elevated PtdIns(3)P produced by the VPS34 complex, which promotes autophagosome formation. TMEM39A knockdown, phosphoinositide measurement, autophagy flux assays Molecular cell High 31806350
2019 TMEM39A/SUSR2 depletion elevates late endosomal/lysosomal PtdIns(4)P levels, facilitating recruitment of the HOPS complex to promote SNARE complex assembly for autophagosome maturation, and also increases lysosomal degradative capability. TMEM39A knockdown, PtdIns(4)P lipid measurement, HOPS complex recruitment assays, SNARE assembly assays, lysosomal activity assays Molecular cell High 31806350
2021 TMEM39A interacts with the dynein intermediate light chain DYNC1I2 to maintain proper perinuclear lysosome distribution; loss of TMEM39A causes redistribution of lysosomes from the perinuclear region to the cell periphery in mammalian cells. Co-immunoprecipitation (TMEM39A–DYNC1I2 interaction), loss-of-function experiments in C. elegans (tmem-39 mutants) and mammalian cells with lysosome localization readout Proceedings of the National Academy of Sciences of the United States of America Medium 33531362
2021 Loss of tmem-39 (C. elegans ortholog of TMEM39A) impairs mTOR signaling and activates the downstream TFEB-like transcription factor HLH-30, linking TMEM39A to lysosome-associated signaling. Genetic loss-of-function (tmem-39 mutants in C. elegans), mTOR pathway readouts, HLH-30/TFEB reporter assays Proceedings of the National Academy of Sciences of the United States of America Medium 33531362
2021 Loss of tmem-39 in C. elegans leads to lysosome tubularization, reduced lysosome mobility, and accumulation of the lysosome-associated membrane protein LMP-1. Live imaging and genetic loss-of-function in C. elegans tmem-39 mutants Proceedings of the National Academy of Sciences of the United States of America Medium 33531362
2024 TMEM39A co-localizes with the COPII coat complex in large vesicles (TMEM39A-LVs) and cooperates with TMEM131 to facilitate bulk secretion of extracellular matrix components (collagens, dual oxidase, carboxypeptidases) through large COPII vesicle formation. Immunoprecipitation of TMEM39A-FLAG followed by proteomics (identifying TMEM131 as interactor), TMEM131 knockdown with collagen secretion readout, co-localization imaging in C. elegans and human sarcoma cells Journal of genetics and genomics Medium 39521045

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. American journal of human genetics 156 22464253
2019 The ER-Localized Transmembrane Protein TMEM39A/SUSR2 Regulates Autophagy by Controlling the Trafficking of the PtdIns(4)P Phosphatase SAC1. Molecular cell 39 31806350
2011 Replication study of 10 genes showing evidence for association with multiple sclerosis: validation of TMEM39A, IL12B and CBLB [correction of CLBL] genes. Multiple sclerosis (Houndmills, Basingstoke, England) 25 22194214
2017 TMEM39A and Human Diseases: A Brief Review. Toxicological research 22 28744351
2021 The conserved autoimmune-disease risk gene TMEM39A regulates lysosome dynamics. Proceedings of the National Academy of Sciences of the United States of America 8 33531362
2019 Genetic Variants in TMEM39A Gene Are Associated with Autoimmune Thyroid Diseases. DNA and cell biology 8 31553233
2017 Association of novel polymorphisms in TMEM39A gene with systemic lupus erythematosus in a Chinese Han population. BMC medical genetics 7 28427360
2024 TMEM39A and TMEM131 facilitate bulk transport of ECM proteins through large COPII vesicle formation. Journal of genetics and genomics = Yi chuan xue bao 6 39521045
2017 Preliminary Study on the Role of TMEM39A Gene in Multiple Sclerosis. Journal of molecular neuroscience : MN 6 28444502
2014 [Correlation between TMEM39A gene polymorphism and systemic lupus erythematosus in Chinese Han patients]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 1 24752108

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