MITD1

MITD1 is an ESCRT-III–interacting protein that functions in the abscission phase of cytokinesis, where its N-terminal MIT domain directly binds the ESCRT-III subunits CHMP1B, CHMP2A, and IST1 to drive recruitment to the midbody (PMID:23015756, PMID:23045692), and its loss destabilizes the midbody and causes abscission failure (PMID:23015756, PMID:23045692). Its C-terminal phospholipase D-like domain mediates both homodimerization and direct membrane binding, properties resolved by crystallography that are important for MITD1 function (PMID:23045692, PMID:23015756). Mechanistically, MITD1 negatively regulates the IST1–VPS4 interaction, positioning it as a modulator of VPS4-driven ESCRT filament remodeling during abscission (PMID:23015756). Beyond cytokinesis, MITD1 is an interferon-stimulated gene selectively induced in microglia that restricts flavivirus replication by sequestering ESCRT-III subunits required for viral replication-factory formation, and is essential for type I interferon anti-flavivirus activity in human microglial-like cells (PMID:40112111). In renal carcinoma cells, MITD1 is stabilized through an RBCK1–ANKRD35–SUMO2 ubiquitin axis and influences AKT and ERK phosphorylation (PMID:36732658), while its depletion induces ferroptosis via the TAZ/SLC7A11 pathway (PMID:36046690); in trophoblasts MITD1 is a transcriptional target of FOXO4 that protects against ferroptotic lipid peroxidation (PMID:42201761).

1. 2012 High

   Established that MITD1 is a bona fide ESCRT-III interactor recruited to the midbody, answering how an uncharacterized MIT-domain protein engages the cytokinetic machinery.

   Evidence Reciprocal Co-IP/pulldown binding assays with CHMP1B, CHMP2A, IST1 plus midbody localization microscopy, replicated in two concurrent papers

   PMID:23015756 PMID:23045692

   Open questions at the time

   • Relative affinity and stoichiometry of the three ESCRT-III interactions not resolved
   • Structural basis of MIT-domain recognition not defined here
2. 2012 High

   Demonstrated a functional cytokinesis role by showing depletion causes abscission failure, moving MITD1 from a binding partner to a required effector.

   Evidence siRNA knockdown with midbody imaging and abscission phenotype readout, reproduced in two papers

   PMID:23015756 PMID:23045692

   Open questions at the time

   • Precise step within abscission that MITD1 controls not pinpointed
   • Whether the phenotype depends on membrane binding vs ESCRT recruitment not separated
3. 2012 High

   Defined the C-terminal domain architecture, revealing a PLD-like fold that mediates dimerization and membrane binding, explaining how MITD1 couples to membranes.

   Evidence X-ray crystallography of the MITD1 PLD-like dimer plus biochemical dimerization and membrane-binding assays

   PMID:23015756 PMID:23045692

   Open questions at the time

   • Lipid specificity of membrane binding not characterized
   • Whether the PLD-like domain retains catalytic activity not addressed
4. 2012 Medium

   Proposed a regulatory mechanism in which MITD1 tunes ESCRT remodeling by antagonizing the IST1–VPS4 interaction.

   Evidence Binding competition Co-IP/pulldown assays showing MITD1 reduces IST1-VPS4 interaction

   PMID:23015756

   Open questions at the time

   • Single method/single lab for the VPS4-regulation claim
   • Direct consequence on VPS4 ATPase activity in cells not measured
5. 2022 Medium

   Linked MITD1 to ferroptosis control in cancer, showing its loss triggers ferroptotic death via a defined signaling axis.

   Evidence siRNA knockdown with ferroptosis assays and TAZ-overexpression rescue, SLC7A11 Western blot in ccRCC cells

   PMID:36046690

   Open questions at the time

   • Single lab
   • How a cytokinetic ESCRT protein mechanistically connects to TAZ/SLC7A11 not resolved
6. 2023 Medium

   Placed MITD1 within a ubiquitin/SUMO stabilization network governing its protein levels and downstream AKT/ERK signaling in renal carcinoma.

   Evidence Knockdown/overexpression with AKT/ERK phosphorylation readouts and protein interaction assays in ccRCC, in vitro and in vivo

   PMID:36732658

   Open questions at the time

   • Pathway not fully reconstituted in vitro
   • Direct mechanism linking MITD1-ANXA1 to AKT/ERK not detailed
7. 2025 Medium

   Revealed an antiviral role, establishing MITD1 as a brain-enriched interferon-stimulated gene that blocks flavivirus replication by sequestering ESCRT-III.

   Evidence Arrayed ISG screen, viral replication assays, ESCRT-III interaction studies, and IFN-I treatment with MITD1 knockdown in microglial-like cells

   PMID:40112111

   Open questions at the time

   • Single lab
   • Which specific ESCRT-III subunits are rate-limiting for sequestration not fully defined
   • In vivo relevance of microglial restriction not established
8. 2026 Medium

   Identified upstream transcriptional control of MITD1 by FOXO4 in a ferroptosis-protective context in trophoblasts.

   Evidence FOXO4 ChIP-seq promoter binding plus gain/loss-of-function with lipid peroxidation and viability readouts

   PMID:42201761

   Open questions at the time

   • Single lab and not fully reconstituted
   • Molecular mechanism by which MITD1 suppresses lipid peroxidation not defined

• How the conserved ESCRT-III/membrane-binding biochemistry of MITD1 mechanistically connects to its disparate ferroptosis, signaling, and antiviral roles remains unresolved.
• No unifying mechanism linking cytokinetic ESCRT function to ferroptosis/AKT-ERK regulation
• Cell-type specificity of the antiviral vs proliferative roles not reconciled