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Showing MID1IP1 — MIG12 is a alias.

MID1IP1

Mid1-interacting protein 1 · UniProt Q9NPA3

Length
183 aa
Mass
20.2 kDa
Annotated
2026-06-10
12 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MID1IP1 (MIG12) is a small cytosolic protein that functions as a master activator of de novo lipogenesis by directly controlling the polymerization state of acetyl-CoA carboxylase (ACC) (PMID:20457939). It binds ACC and lowers the citrate threshold for ACC polymerization into the physiological range, increasing ACC enzymatic activity more than 50-fold in vitro and driving hepatic fatty acid synthesis and triglyceride accumulation upon overexpression (PMID:20457939); the ACC interaction and polymerization-stimulating activity are mediated by its leucine-zipper domain (PMID:34153683). This lipogenic activity is embedded in transcriptional and signaling circuits: MID1IP1 is a direct transcriptional target of LXRα/RXRα and ChREBP through dedicated promoter elements, coupling sterol and carbohydrate sensing to ACC activation (PMID:21474539), and it acts upstream of AMPK to suppress AMPK phosphorylation (PMID:30700011). The same factor that activates ACC can also be restrained: in a heterocomplex with Spot14 it sequesters ACC2 and blocks the nucleation step of polymer formation (PMID:24277613). Independently of lipogenesis, MID1IP1 interacts with MID1 via the MID1 coiled-coil domain and is recruited to stabilized, acetylated-tubulin microtubule bundles, cooperating with MID1 in microtubule stabilization (PMID:15070402). In cancer cells MID1IP1 promotes growth by stabilizing c-Myc through suppression of the ribosomal proteins L5 and L11 (PMID:32316188), and acts as a required mediator linking CNOT2 inhibition to p53 induction and apoptosis (PMID:34680125).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 High

    Established the first molecular partner of MID1IP1, showing it is not a free cytosolic protein but a cofactor that cooperates with MID1 on the microtubule cytoskeleton.

    Evidence Yeast two-hybrid, co-IP, and co-transfection immunofluorescence showing recruitment to acetylated microtubule bundles

    PMID:15070402

    Open questions at the time
    • Does not define the structural basis of microtubule stabilization
    • Functional consequence of MID1–MID1IP1 microtubule complex in vivo not established
  2. 2010 High

    Defined the core biochemical function of MID1IP1 as a direct activator of ACC polymerization, answering how a small protein could amplify fatty acid synthesis.

    Evidence In vitro reconstitution with recombinant proteins (nondenaturing gels, FPLC, EM) plus hepatic overexpression with metabolic readouts

    PMID:20457939

    Open questions at the time
    • Stoichiometry and structural model of the MID1IP1–ACC polymer not resolved
    • Did not identify the protein interaction interface
  3. 2011 High

    Placed MID1IP1 within lipogenic transcriptional control by identifying LXRα/RXRα and ChREBP as direct upstream regulators, explaining how nutrient and sterol signals engage ACC activation.

    Evidence Luciferase reporters, EMSA, promoter mutagenesis, and KD/OE in primary hepatocytes with lipid synthesis readouts

    PMID:21474539

    Open questions at the time
    • Does not address post-transcriptional regulation of MID1IP1
    • Relative contribution of LXR versus ChREBP inputs in vivo unclear
  4. 2013 Medium

    Revealed that MID1IP1 can also inhibit ACC, showing that in a Spot14 heterocomplex it sequesters ACC2 and blocks polymer nucleation — a context-dependent reversal of its activating role.

    Evidence Atomic force microscopy and in vitro enzymatic assays with purified recombinant proteins

    PMID:24277613

    Open questions at the time
    • Single lab, limited mechanistic depth
    • Physiological conditions that favor activating versus inhibitory complexes not defined
  5. 2019 Medium

    Positioned MID1IP1 upstream of AMPK in lipogenic signaling, connecting its ACC-centric role to a broader energy-sensing axis.

    Evidence siRNA KD/OE in HepG2, phospho-AMPK/ACC Western blots, and pharmacological epistasis with compound C

    PMID:30700011

    Open questions at the time
    • Mechanism by which MID1IP1 suppresses AMPK phosphorylation unknown
    • No direct physical link between MID1IP1 and AMPK shown
  6. 2021 Medium

    Mapped the ACC-binding and polymerization-stimulating activity to the MID1IP1 leucine-zipper domain, identifying the functional interface for its lipogenic role.

    Evidence Leucine-zipper mutagenesis with interaction and polymerization assays plus KD epistasis downstream of LXR in HepG2

    PMID:34153683

    Open questions at the time
    • No co-crystal or high-resolution structure of the interface
    • Single lab
  7. 2020 Medium

    Extended MID1IP1 function to oncogenesis by showing it stabilizes c-Myc through suppression of ribosomal proteins L5 and L11.

    Evidence siRNA KD/OE, L5/L11 rescue, immunofluorescence colocalization, and tissue arrays in HCC cell lines

    PMID:32316188

    Open questions at the time
    • How MID1IP1 suppresses L5/L11 is not defined
    • Direct versus indirect regulation of c-Myc unresolved
  8. 2021 Medium

    Identified MID1IP1 as a required downstream mediator of CNOT2-dependent p53 activation and apoptosis, linking it to tumor suppressor signaling.

    Evidence MID1IP1/CNOT2 double knockdown with apoptosis and p53 half-life assays in colorectal cancer cells

    PMID:34680125

    Open questions at the time
    • Single method per node
    • Molecular mechanism connecting MID1IP1 to p53 stability not shown
  9. 2025 Low

    Connected MID1IP1 loss to ferroptotic cell death, proposing that its c-Myc/glycolysis axis maintains GPX4 and ferroptosis resistance in colorectal cancer.

    Evidence siRNA KD, ROS probes, GPX4 Western blots, and ferroptosis inhibitor rescue in HCT116 cells

    PMID:41343117

    Open questions at the time
    • Single lab, single method per endpoint, no reconstitution or epistasis beyond inhibitor rescue
    • Causal chain from MID1IP1 to GPX4 not mechanistically established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MID1IP1 reconciles its dual ACC-activating versus ACC-sequestering roles and whether its cytoskeletal and oncogenic functions share a common biochemical activity remain unresolved.
  • No structural model integrating ACC, MID1, and partner binding via the leucine-zipper
  • Whether the microtubule and lipogenic functions are mechanistically linked is unknown
  • Direct physical partners in the c-Myc, AMPK, and p53 axes not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-162582 Signal Transduction 1
Partners
ACACACNOT2MID1THRSP
Complex memberships
Spot14/MIG12 heterocomplex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 MIG12 (MID1IP1) binds directly to acetyl-CoA carboxylase (ACC) and lowers the threshold for citrate-induced ACC polymerization into the physiological range (<1 mM), increasing ACC enzymatic activity >50-fold in vitro; in vivo overexpression of MIG12 in liver induced ACC polymerization, increased fatty acid synthesis, and produced triglyceride accumulation. In vitro recombinant protein binding and polymerization assays (nondenaturing gels, FPLC, electron microscopy), in vivo hepatic overexpression with metabolic readouts Proceedings of the National Academy of Sciences of the United States of America High 20457939
2004 MIG12 (MID1IP1) physically interacts with MID1 via the MID1 coiled-coil domain (confirmed by yeast two-hybrid and co-immunoprecipitation); when co-expressed with MID1, Mig12 is massively recruited to thick microtubule bundles composed of acetylated (stabilized) tubulin that are resistant to high doses of depolymerizing agents, indicating Mig12 cooperates with MID1 to stabilize microtubules. Yeast two-hybrid screening, co-immunoprecipitation, co-transfection/immunofluorescence, biochemical microtubule fractionation, drug resistance assay BMC cell biology High 15070402
2011 MIG12 (MID1IP1) gene is a transcriptional target of LXRα/RXRα via a functional LXR-responsive element (LXRE3) and of ChREBP via a carbohydrate response element in its promoter; MIG12 overexpression stimulated and MIG12 knockdown attenuated LXR ligand-stimulated de novo fatty acid synthesis and triacylglycerol accumulation in hepatocytes. Luciferase reporter assays, EMSA (LXRα/RXRα binding to LXRE3), promoter deletion/mutation analysis, overexpression and knockdown in primary hepatocytes with lipid synthesis readouts Molecular endocrinology (Baltimore, Md.) High 21474539
2013 The Spot14/Mig12 (MID1IP1) heterocomplex restrains citrate-induced polymerization and enzymatic activity of ACC2 in vitro by sequestering ACC2 and preventing the initial nucleation step of filamentous polymer formation; the full heterocomplex is more inhibitory than an oligo-heterocomplex. Atomic force microscopy for nanoscale protein topography, in vitro enzymatic activity assays with purified recombinant proteins Journal of molecular recognition : JMR Medium 24277613
2019 MID1IP1 acts upstream of AMPK: MID1IP1 depletion activates AMPK phosphorylation, while MID1IP1 overexpression suppresses AMPK phosphorylation in HepG2 cells; AMPK inhibition (compound C) does not alter MID1IP1 expression, placing MID1IP1 upstream of AMPK in lipogenic signaling. siRNA knockdown and overexpression in HepG2 cells, Western blotting for phospho-AMPK/ACC, pharmacological epistasis with AMPK inhibitor compound C International journal of molecular sciences Medium 30700011
2021 MIG12 (MID1IP1) stimulates ACC polymerization downstream of LXR activation in HepG2 cells; mutations in MIG12's leucine-zipper domain reduce the MIG12–ACC interaction and decrease MIG12's capacity to stimulate ACC polymerization, identifying the leucine-zipper domain as the functional interface. MID1IP1 knockdown (abrogation of LXR-stimulated ACC polymerization), leucine-zipper domain mutagenesis with interaction and polymerization assays in HepG2 cells Biochemical and biophysical research communications Medium 34153683
2020 MID1IP1 promotes liver cancer cell growth by stabilizing c-Myc; mechanistically, MID1IP1 depletion upregulates ribosomal proteins L5 and L11, which destabilize c-Myc, and re-expression of L5 or L11 rescues c-Myc levels in MID1IP1-depleted cells. MID1IP1 and c-Myc colocalize in HCC cells and tissues. siRNA knockdown, overexpression, L5/L11 rescue experiments, immunofluorescence colocalization, tissue array, Western blotting in HepG2 and Huh7 cells Cells Medium 32316188
2021 CNOT2 inhibition cannot induce p53 expression or apoptosis in colorectal cancer cells in the absence of MID1IP1, placing MID1IP1 as a required mediator downstream of CNOT2 for p53 activation. MID1IP1 siRNA knockdown combined with CNOT2 inhibition, apoptosis assays, p53 half-life measurement in cancer cells Biomolecules Medium 34680125
2025 MID1IP1 knockdown in HCT116 colorectal cancer cells reduces c-Myc stability, decreases glycolysis-related protein expression, reduces GPX4 and other ferroptosis-protective proteins, and leads to ROS accumulation and ferroptotic cell death; a ferroptosis inhibitor confirmed the ferroptotic mechanism. siRNA knockdown, Western blotting, ROS fluorescence probe, ferroptosis inhibitor rescue, immunofluorescence in HCT116 cells Genes & genomics Low 41343117

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis. Proceedings of the National Academy of Sciences of the United States of America 122 20457939
2004 Mig12, a novel Opitz syndrome gene product partner, is expressed in the embryonic ventral midline and co-operates with Mid1 to bundle and stabilize microtubules. BMC cell biology 57 15070402
2012 The filamentous growth MAPK Pathway Responds to Glucose Starvation Through the Mig1/2 transcriptional repressors in Saccharomyces cerevisiae. Genetics 48 22904036
2019 Hypolipogenic Effect of Shikimic Acid Via Inhibition of MID1IP1 and Phosphorylation of AMPK/ACC. International journal of molecular sciences 34 30700011
2020 Colocalization of MID1IP1 and c-Myc is Critically Involved in Liver Cancer Growth via Regulation of Ribosomal Protein L5 and L11 and CNOT2. Cells 32 32316188
2021 Inhibition of CNOT2 Induces Apoptosis via MID1IP1 in Colorectal Cancer Cells by Activating p53. Biomolecules 22 34680125
2013 Spot14/Mig12 heterocomplex sequesters polymerization and restrains catalytic function of human acetyl-CoA carboxylase 2. Journal of molecular recognition : JMR 22 24277613
2011 Identification of MIG12 as a mediator for stimulation of lipogenesis by LXR activation. Molecular endocrinology (Baltimore, Md.) 22 21474539
2021 MIG12 is involved in the LXR activation-mediated induction of the polymerization of mammalian acetyl-CoA carboxylase. Biochemical and biophysical research communications 5 34153683
2022 Hypolipogenic effects of Icariside E4 via phosphorylation of AMPK and inhibition of MID1IP1 in HepG2 cells. Phytotherapy research : PTR 4 35916211
2024 Roles of a newly lethal cuticular structural protein, AaCPR100A, and its upstream interaction protein, G12-like, in Aedes aegypti. International journal of biological macromolecules 3 38670198
2025 Inhibition of MID1IP1 induces ferroptosis and suppresses c-Myc expression in colorectal cancer cell. Genes & genomics 0 41343117

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