MIOS

MIOS (YULINK/Sea4) is a WD40-repeat subunit of the GATOR2 complex that promotes mTORC1 activation within nutrient-sensing pathways (PMID:38898112, PMID:38928292). In the SESN–GATOR2–mTORC1 axis, MIOS acts downstream of sestrin 2 and is required for inhibition of mTORC1 and induction of autophagy, since its ablation in Dictyostelium abolished both responses (PMID:38928292); in zebrafish oogenesis it functions as an essential GATOR2-mediated checkpoint downstream of Rbpms2 to drive mTORC1-dependent nucleolar amplification and oocyte fate (PMID:38898112). Beyond this canonical role, MIOS engages glucose-handling and trafficking machinery: it physically interacts with the glucose transporter GLUT1 and is required for GLUT1 expression and translocation from cytosol to the plasma membrane, thereby supporting glucose uptake and glycolysis (PMID:41013205), and it associates with endocytic proteins EPS15, RAB33B, TICAM2, Clathrin and RHOB to support VEGF-induced VEGFR2 internalization and vascular formation (PMID:36843032). In cardiomyocytes, MIOS regulates SERCA2 expression through a PPARγ-dependent mechanism, controlling Ca2+ reuptake (PMID:33423678).

1. 2018 Low

   An initial question was whether MIOS/YULINK has a role in cardiac calcium handling; loss-of-function linked it to SERCA2 expression and Ca2+ cycling, but the founding report was later retracted.

   Evidence Morpholino knockdown in zebrafish and shRNA in mouse cardiomyocytes with PPARγ activity and Ca2+ imaging (retracted)

   PMID:29401584

   Open questions at the time

   • Original report retracted; cannot be trusted independently
   • Mechanism connecting MIOS to PPARγ not defined at the molecular level
2. 2021 Medium

   Re-establishing the cardiac role with non-retracted data clarified that MIOS controls SERCA2 expression specifically through promoting PPARγ nuclear/DNA-binding activity.

   Evidence shRNA knockdown in HL-1 cardiomyocytes with PPARγ DNA-binding assay, agonist rescue, PPARγ-shRNA phenocopy, and Ca2+ imaging

   PMID:33423678

   Open questions at the time

   • How MIOS regulates PPARγ activity mechanistically is unresolved
   • No demonstrated direct physical interaction between MIOS and PPARγ
3. 2023 Medium

   Whether MIOS participates in membrane trafficking was tested in endothelial cells, showing it physically associates with endocytic machinery to enable receptor internalization.

   Evidence Yeast two-hybrid, FLIM-FRET, IP and immunofluorescence in HUVECs, with VEGFR2 internalization assays and zebrafish knockdown

   PMID:36843032

   Open questions at the time

   • Direct vs. scaffolding role within the endocytic complex not resolved
   • Relationship between this trafficking function and GATOR2/mTORC1 role unknown
4. 2023 Low

   A parallel study placed MIOS upstream of PI3K-AKT signaling in vascular smooth muscle, linking it to migration, proliferation and glycolysis.

   Evidence shRNA knockdown and overexpression in PASMCs with western blot of pathway components, glucose uptake and migration assays

   PMID:38057829

   Open questions at the time

   • Pathway placement inferred from KD readouts without direct binding evidence for PI3K-AKT components
   • Mechanism connecting MIOS to PDGFR expression not established
5. 2024 Medium

   The canonical GATOR2/mTORC1 function was established in two systems: MIOS is required downstream of sestrin 2 for mTORC1 inhibition and autophagy, and acts as an mTORC1-activating GATOR2 checkpoint in oocyte fate determination.

   Evidence Genetic ablation in Dictyostelium with mTORC1 and autophagy readouts; genetic epistasis with Rbpms2 in zebrafish oogenesis (plus corroborating preprint)

   PMID:38328218 PMID:38898112 PMID:38928292

   Open questions at the time

   • Structural basis of MIOS within GATOR2 in these systems not addressed
   • Whether nutrient-sensing and trafficking/cardiac roles are mechanistically connected is unknown
6. 2025 Medium

   Whether MIOS directly controls a glucose transporter was answered by showing physical interaction with GLUT1 and a requirement for GLUT1 membrane translocation, tying MIOS to glycolytic metabolism.

   Evidence Proximity ligation assay and IP for interaction; immunofluorescence, glucose uptake and glycolytic assays in Huh7 HCC cells

   PMID:41013205

   Open questions at the time

   • Mechanism by which MIOS drives GLUT1 trafficking not defined
   • Relationship to MIOS endocytic/GATOR2 functions unresolved

• It remains unknown how MIOS's GATOR2/mTORC1 nutrient-sensing function relates mechanistically to its reported roles in GLUT1 trafficking, endocytic VEGFR2 internalization, and PPARγ-dependent SERCA2 regulation.
• No structural model of MIOS in human cells
• Whether trafficking and metabolic roles are mTORC1-dependent is untested
• Direct binding partners bridging these functions not identified