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Showing MIA2 — CTAGE5 is a alias.

MIA2

Melanoma inhibitory activity protein 2 · UniProt Q96PC5

Length
1412 aa
Mass
159.8 kDa
Annotated
2026-06-10
22 papers in source corpus 12 papers cited in narrative 12 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

MIA2 (also known as cTAGE5/MEA6, with the transmembrane fusion isoform TALI) is a resident ER exit-site protein that organizes COPII-dependent export of secretory cargo from the endoplasmic reticulum (PMID:21807889, PMID:27311593). Its cytosolic C-terminus directly binds the COPII inner-coat proteins Sec23 and Sec24, and it coordinates productive coat assembly by regulating the SAR1–SEC23 interaction; loss of the protein causes persistent SAR1 activation and blocks ER-to-Golgi transport (PMID:21807889, PMID:30224460). A central function is the ER export of bulky and specialized cargo: together with TANGO1, MIA2/TALI binds apolipoprotein B and is required to recruit and export ApoB-containing lipid particles (pre-VLDLs/pre-chylomicrons), whereas procollagen export in the same cells depends only on TANGO1 (PMID:27138255). Consistent with this, hepatic loss-of-function disrupts secretion of VLDL and other lipoproteins, producing fatty liver and dyslipidemia (PMID:21807889, PMID:27311593). In the nervous system the protein is required for ER export of signaling and synaptic cargoes—Slit2, BDNF, and VGLUT1—and its loss disrupts dendrite and synapse development, cerebellar function, oligodendrocyte differentiation, and myelin lipid composition (PMID:30224460, PMID:31244610, PMID:33718348, PMID:39872732). Beyond ER exit sites it interacts with TRAPPC12 to control COPII component distribution and with the lamin B receptor (LBR) to maintain inner nuclear membrane localization and nuclear envelope integrity, with loss driving cellular senescence via the P53/P21 pathway (PMID:38439956, PMID:40739853). Hepatic MIA2 expression is driven by HNF-1 and induced by IL-6 and TGF-β (PMID:12586826).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 Medium

    Established how MIA2 transcription is controlled, identifying the cis-regulatory basis for its hepatocyte-restricted expression and its responsiveness to inflammatory and fibrogenic signals.

    Evidence Promoter reporter assays, site-directed mutagenesis, and cytokine stimulation in HepG2 cells

    PMID:12586826

    Open questions at the time
    • Did not address protein function or subcellular role
    • SMAD/STAT3 site occupancy inferred from sequence, not direct binding
  2. 2007 Medium

    Linked MIA2 expression to HCC behavior, showing re-expression suppresses proliferation and invasion, raising a possible tumor-suppressive role downstream of HNF-1.

    Evidence Promoter mutagenesis, HCC cell transfection, invasion/proliferation assays, nude mouse xenografts, recombinant protein treatment

    PMID:17881540

    Open questions at the time
    • Molecular mechanism of growth suppression unresolved
    • Relationship between secretory function and tumor phenotype not established
    • Single lab
  3. 2011 High

    Defined MIA2 as an ER exit-site protein that directly binds COPII coat components and regulates systemic lipid metabolism, converting a transcription-focused gene into a trafficking factor.

    Evidence Forward genetic screen (couch potato mutant), subcellular fractionation, direct Sec23/Sec24 binding assay, plasma lipoprotein fractionation in mice

    PMID:21807889

    Open questions at the time
    • Did not establish the cargo selectivity mechanism
    • Role of TANGO1 cooperation not yet defined
  4. 2016 High

    Resolved the cargo logic of ER export: MIA2/TALI cooperates with TANGO1 and binds ApoB to selectively export lipoprotein particles, distinguishing this pathway from TANGO1-only collagen export.

    Evidence Co-IP, siRNA knockdown with cargo-export readouts, cell fractionation (TALI study); conditional hepatocyte KO with lipidomics, proteomics, and COPII Co-IP (cTAGE5 study)

    PMID:27138255 PMID:27311593

    Open questions at the time
    • Stoichiometry and assembly order of the TANGO1/TALI/COPII machinery unresolved
    • How bulky cargo size is sensed not defined
  5. 2018 High

    Provided the COPII regulatory mechanism, showing the protein controls the SAR1–SEC23 interaction and that its loss causes persistent SAR1 activation and trafficking failure in neurons.

    Evidence Brain-specific conditional KO mice, Co-IP of SAR1/SEC23, trafficking assays, morphological and behavioral analyses

    PMID:30224460

    Open questions at the time
    • Direct biochemical mechanism of SAR1 cycling regulation not reconstituted
    • Generalizability beyond neurons to other cargoes untested
  6. 2021 Medium

    Extended the neuronal role to defined cargoes (Slit2, BDNF, VGLUT1) across cerebellar cell types, establishing the protein as essential for secretion of specific developmental and synaptic factors.

    Evidence Purkinje-cell, pan-neuronal, and granule-cell conditional KO mice; IHC for ER-retained cargo; behavioral testing

    PMID:31244610 PMID:33718348

    Open questions at the time
    • Whether cargo selectivity reflects direct interactions or general COPII dependence unclear
    • Single lab
  7. 2024 Medium

    Identified TRAPPC12 as an ER exit-site partner controlling COPII component distribution, and showed pleiotrophin secretion underlies the oligodendrocyte differentiation requirement.

    Evidence Co-IP, conditional KO in OPCs, immunofluorescence for COPII components, rescue with exogenous PTN

    PMID:38439956

    Open questions at the time
    • Functional hierarchy between MEA6 and TRAPPC12 at exit sites unresolved
    • Single lab
  8. 2025 Medium

    Revealed a non-canonical role beyond ER exit sites: direct interaction with LBR maintains inner nuclear membrane localization and nuclear envelope integrity, with loss driving P53/P21-dependent senescence and premature aging.

    Evidence Conditional KO mice, Co-IP of cTAGE5 with LBR, LBR localization imaging, MEF senescence and P53/P21 assays (aging study); medaka CRISPR KO of TALI isoform with collagen export readout (species comparison)

    PMID:39842788 PMID:40739853

    Open questions at the time
    • Mechanism linking nuclear envelope defects to senescence not fully dissected
    • Medaka data indicate TALI is dispensable for large cargo export in fish, leaving species-specific requirements unexplained
    • Single lab per finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the protein integrates its ER exit-site COPII function with its nuclear envelope (LBR) role, and how cargo selectivity is achieved mechanistically, remain open.
  • No reconstituted biochemistry defining SAR1/SEC23 regulation
  • Structural basis of TANGO1/TALI/ApoB recruitment unknown
  • Reconciliation of mammalian vs. medaka cargo-export requirements unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0038024 cargo receptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005635 nuclear envelope 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9609507 Protein localization 3 R-HSA-392499 Metabolism of proteins 2
Partners
APOBLBRSAR1SEC23SEC24TANGO1TRAPPC12

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 TALI (MIA2/cTAGE5 fusion product) physically binds TANGO1, and both interact with apolipoprotein B (ApoB). TANGO1 and TALI are both required for recruitment of ApoB-containing lipid particles (pre-chylomicrons/pre-VLDLs) to ER exit sites and their subsequent export from the ER, whereas procollagen XII export by the same cells requires only TANGO1. Co-immunoprecipitation, siRNA knockdown with cargo-export readouts, cell fractionation The Journal of cell biology High 27138255
2011 Mia2 localizes to ER exit sites in hepatocytes. Its cytosolic C-terminus directly interacts with COPII proteins Sec23 and Sec24. A recessive point mutation (couch potato) in the SH3 domain of Mia2 reduces plasma VLDL, LDL, HDL, and triglycerides in mice, establishing Mia2 as a hepatic ER-to-Golgi trafficking protein regulating cholesterol and lipid metabolism. Forward genetic screen in mice, subcellular fractionation/localization, direct binding assay with COPII proteins (Sec23/Sec24), plasma lipoprotein fractionation Journal of lipid research High 21807889
2016 Hepatocyte-specific deletion of Mea6/cTAGE5 in mice causes severe fatty liver and hypolipemia. Mea6/cTAGE5 interacts with COPII components, and its loss impairs secretion of lipids (including VLDL) and proteins from the liver, demonstrating a critical role in coordinating COPII assembly for ER-to-Golgi lipid transport. Conditional knockout mice, quantitative lipidomics, quantitative proteomics, co-immunoprecipitation with COPII components Cell research High 27311593
2018 Conditional knockout of cTAGE5/MEA6 in the brain reveals it is required for COPII vesicle formation by regulating the interaction between SAR1 and SEC23; its loss leads to persistent SAR1 activation, defective ER-to-Golgi transport, impaired trafficking of membrane components in neurons, and severe defects in dendrite outgrowth, spine formation, and astrocyte activation. Conditional knockout mice (brain-specific), co-immunoprecipitation of COPII components (SAR1, SEC23), intracellular trafficking assays, morphological and behavioral analyses Proceedings of the National Academy of Sciences of the United States of America High 30224460
2007 MIA2 expression in hepatocytes is driven by HNF-1 binding to its promoter at position -236. Loss of HNF-1 in HCC reduces MIA2 expression. Re-expression of MIA2 in HCC cells reduces invasive potential and proliferation in vitro and in vivo. Recombinant MIA2 protein also inhibits HCC cell proliferation and invasion. Promoter mutagenesis, stable transfection of HCC cell lines, invasion assays, proliferation assays, nude mouse xenograft model, recombinant protein treatment Gut Medium 17881540
2003 MIA2 promoter contains an HNF-1 binding site at position -236 that controls hepatocyte-specific expression; mutation of this site abolishes promoter activity in HepG2 cells. SMAD and STAT3 binding sites are also present, and MIA2 mRNA is induced by IL-6, TGF-β, and conditioned medium from activated hepatic stellate cells. Promoter reporter assays, site-directed mutagenesis, RT-PCR, cytokine stimulation experiments The Journal of biological chemistry Medium 12586826
2019 MEA6/cTAGE5 ablation in Purkinje cells or all neurons leads to arrested secretory proteins (Slit2, BDNF) in the ER, establishing that MEA6 is required for ER export of these signaling proteins in the cerebellum and that its loss disrupts cerebellar development and motor performance. Conditional knockout mice (Nestin-Cre and pCP2-Cre), immunohistochemistry for ER-retained proteins, behavioral tests Frontiers in cellular neuroscience Medium 31244610
2021 Deletion of Mea6 specifically in cerebellar granule cells impairs intracellular transport of vesicular glutamate transporter 1 (VGLUT1) and BDNF, disrupts parallel fiber-Purkinje cell synaptic development, and causes abnormal motor behavior, indicating Mea6 is required for trafficking of synaptic components in granule cells. Math1-Cre conditional knockout mice, immunohistochemistry, behavioral tests (rotarod, balance beam) Frontiers in cell and developmental biology Medium 33718348
2023 Conditional knockout of Mea6/cTAGE5 in oligodendrocytes impairs white matter microstructure and significantly alters myelin lipid composition, particularly reducing very long chain fatty acid (VLCFA)-containing phosphatidylcholines, likely due to downregulated ELOVL elongase expression. Conditional knockout mice, diffusion MRI, lipidomic analysis of purified myelin sheath Life metabolism Medium 39872732
2024 Mea6/cTAGE5 interacts with TRAPPC12, and both localize to ER exit sites where they regulate COPII component distribution (SEC13, SEC31A, SAR1). Loss of Mea6 in oligodendrocyte progenitor cells (OPCs) disrupts TRAPPC12 distribution and impairs secretion of pleiotrophin (PTN); exogenous PTN supplementation rescues OPC differentiation deficits. Co-immunoprecipitation, conditional knockout mice, rescue experiment with exogenous PTN, immunofluorescence for COPII components iScience Medium 38439956
2025 cTAGE5/MEA6 localizes not only to ER exit sites but also to other ER structures where it directly interacts with the lamin B receptor (LBR). Loss of cTAGE5 disrupts LBR localization to the inner nuclear membrane (causing its ER retention and instability), leading to abnormal nuclear envelope morphology, cellular senescence via the P53/P21 pathway, premature aging, and embryonic lethality in conditional knockout mice. Conditional knockout mice, co-immunoprecipitation of cTAGE5 with LBR, immunofluorescence for LBR localization, MEF cell senescence assays, P53/P21 pathway analysis Aging cell Medium 40739853
2025 In medaka fish, knockout of Tali (the MIA2-encoded transmembrane isoform) does not produce a lethal phenotype and does not impair export of type II collagen from the ER, indicating that in this vertebrate model Tali is dispensable for large cargo export (in contrast to findings in mammalian systems). CRISPR/Cas9 knockout of individual splicing variants (Tali-KO, cTAGE5-KO) in medaka fish, collagen export assays Cell structure and function Medium 39842788

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 TANGO1 and Mia2/cTAGE5 (TALI) cooperate to export bulky pre-chylomicrons/VLDLs from the endoplasmic reticulum. The Journal of cell biology 95 27138255
1994 Isolation, sequence and expression of a novel mouse brain cDNA, mIA-2, and its relatedness to members of the protein tyrosine phosphatase family. Biochemical and biophysical research communications 64 7980563
2007 The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma. Gut 57 17881540
2016 Mea6 controls VLDL transport through the coordinated regulation of COPII assembly. Cell research 42 27311593
2003 Specific expression and regulation of the new melanoma inhibitory activity-related gene MIA2 in hepatocytes. The Journal of biological chemistry 42 12586826
2011 Reduced cholesterol and triglycerides in mice with a mutation in Mia2, a liver protein that localizes to ER exit sites. Journal of lipid research 35 21807889
2018 cTAGE5/MEA6 plays a critical role in neuronal cellular components trafficking and brain development. Proceedings of the National Academy of Sciences of the United States of America 22 30224460
2008 TALI: local alignment of protein structures using backbone torsion angles. Journal of bioinformatics and computational biology 15 18324751
2011 Assessment of GFP expression and viability using the tali image-based cytometer. Journal of visualized experiments : JoVE 13 22127256
2025 Novel humanized CD19-CAR-T (Now talicabtagene autoleucel, Tali-cel™) cells in relapsed/ refractory pediatric B-acute lymphoblastic leukemia- an open-label single-arm phase-I/Ib study. Blood cancer journal 9 40274761
2019 MEA6 Deficiency Impairs Cerebellar Development and Motor Performance by Tethering Protein Trafficking. Frontiers in cellular neuroscience 9 31244610
2021 Deletion of Mea6 in Cerebellar Granule Cells Impairs Synaptic Development and Motor Performance. Frontiers in cell and developmental biology 8 33718348
2002 Characterization of the elusive disulfide bridge forming human Hb variant: Hb Ta-Li beta83 (EF7)Gly --> Cys by electrospray mass spectrometry. Journal of the American Society for Mass Spectrometry 8 11838022
2023 Ablation of Mea6/cTAGE5 in oligodendrocytes significantly impairs white matter structure and lipid content. Life metabolism 6 39872732
2022 Molecular mechanisms underlying cTAGE5/MEA6-mediated cargo transport and biological functions. Journal of genetics and genomics = Yi chuan xue bao 5 35436610
2022 CircNRIP1 acts as a sponge of miR-1200 to suppress osteosarcoma progression via upregulation of MIA2. American journal of cancer research 5 35812061
2024 Mea6/cTAGE5 cooperates with TRAPPC12 to regulate PTN secretion and white matter development. iScience 3 38439956
2021 Determine genetic variations in heat shock factor gene family (HSFs) and study their effect on the functional and structural characterization of protein in Tali goat. Animal biotechnology 3 34370605
2025 Tango1L but not Tango1S, Tali and cTAGE5 is required for export of type II collagen in medaka fish. Cell structure and function 2 39842788
2023 Identification genetic variations in some heat shock protein genes of Tali goat breed and study their structural and functional effects on relevant proteins. Veterinary medicine and science 2 37530404
2006 [Osteonecroses of the bilateral tali during maintenance therapy in a child with acute lymphoblastic leukemia]. [Rinsho ketsueki] The Japanese journal of clinical hematology 1 16529012
2025 cTAGE5/MEA6 Regulates LBR Localization to Maintain Nuclear Envelope Integrity and Safeguard Against Aging. Aging cell 0 40739853

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