MYO1F

MYO1F is a long-tailed class I unconventional myosin expressed predominantly in immune cells that functions at the cortical actin–plasma membrane interface to coordinate cell adhesion, migration, exocytosis, and innate immune signaling. It acts as a kinase-responsive scaffold: SYK and LCK phosphorylate MYO1F, which then recruits acetyltransferases (αTAT1, KAT2A) to specific substrates—α-tubulin for Dectin-1/CARD9 antifungal signaling, cGAS for type I interferon production, and GAPDH for glycolytic reprogramming in T cells (PMID:34301894, PMID:39694035, PMID:39668163). MYO1F localizes to podosomes and phagocytic cups through SH3-domain interactions with the CASS adaptor complex (CD2AP, ASAP1, SH3BP2, SH3KBP1) and PH-domain membrane contacts, and recruits EPLINα to stabilize F-actin and drive MRTFA-dependent integrin β2 transcription, linking cortical cytoskeletal dynamics to integrin-mediated adhesion and migration (PMID:41208482, PMID:41610517). Loss of Myo1f in neutrophils causes augmented granule exocytosis with increased adhesion and reduced motility, while in tumor-associated neutrophils its epigenetic silencing by TGF-β1 derepresses STAT3-dependent immunosuppression (PMID:17023661, PMID:40202509).

1. 2006 High

   Establishing the foundational role: Myo1f knockout mice revealed that this class I myosin negatively regulates neutrophil granule exocytosis and positively supports cell motility, providing the first evidence that a myosin-I controls immune cell adhesion–migration balance at the cortical actin interface.

   Evidence Myo1f KO mouse with FACS adhesion assays, exocytosis measurements, and in vivo infection model (Science)

   PMID:17023661

   Open questions at the time

   • Molecular mechanism by which Myo1f restrains granule fusion was not identified
   • Whether Myo1f directly contacts integrin-containing vesicles or acts indirectly through cortical actin was unclear
2. 2018 Medium

   A motor-domain missense mutation (Gly134Ser) near the ATP-binding site demonstrated that MYO1F motor integrity influences mitochondrial morphology, ROS levels, and cellular proliferation, broadening its functional scope beyond canonical actin-based roles.

   Evidence Stable expression of WT vs. mutant MYO1F in thyroid cells with mitochondrial staining, ROS assays, and zebrafish overexpression

   PMID:29672841

   Open questions at the time

   • Whether MYO1F directly localizes to mitochondria or acts indirectly was not resolved
   • Relevance to immune cell biology was not tested
   • No structural model of how G134S alters ATPase activity
3. 2019 Medium

   Identification of SH3BP2 (3BP2) as a direct MYO1F interactor downstream of KIT signaling in mast cells linked MYO1F to receptor tyrosine kinase pathways and provided the first evidence that it controls integrin surface expression and Rac2/Cdc42 activation.

   Evidence Co-immunoprecipitation and shRNA knockdown in mast cells with flow cytometry, GTPase assays, and migration assays

   PMID:31143189

   Open questions at the time

   • Reciprocal Co-IP was not shown
   • Whether MYO1F–3BP2 interaction is direct or bridged by additional adaptors was not confirmed
   • Mechanism by which MYO1F controls integrin surface levels was not defined
4. 2021 High

   A critical mechanistic advance showed MYO1F functions as an adaptor that recruits αTAT1 acetyltransferase to α-tubulin upon Dectin-1 stimulation, with the resulting tubulin acetylation controlling SYK/CARD9 membrane-to-cytoplasm trafficking for antifungal innate immunity—establishing its scaffold/adaptor paradigm.

   Evidence Reciprocal Co-IP, Myo1f KO macrophages, Dectin-1 stimulation, tubulin acetylation blots, in vivo Candida infection model (PNAS)

   PMID:34301894

   Open questions at the time

   • Whether MYO1F motor activity is required for αTAT1 recruitment was not tested
   • Structural basis for the MYO1F–αTAT1–tubulin ternary complex was not determined
5. 2021 Medium

   MYO1F was shown to be required for full mast cell degranulation through IgE/FcεRI and MRGPRX2, controlling Cdc42 activation, cortical actin reassembly, and mitochondrial translocation to exocytic sites, extending the exocytosis phenotype to a defined signaling cascade.

   Evidence shRNA knockdown in human LAD2 mast cells with degranulation assays, Cdc42 activation, confocal imaging, AKT/DRP1 phosphorylation blots

   PMID:33941653

   Open questions at the time

   • Direct versus indirect effect on mitochondrial translocation was not resolved
   • Whether MYO1F interacts directly with DRP1 or mitochondrial fission machinery was not tested
6. 2023 Medium

   Myo1f KO γδT intraepithelial lymphocytes showed reduced CCR9 and α4β7 surface expression with defective chemokine receptor polarization, demonstrating MYO1F controls integrin/receptor polarization and homing across lymphoid lineages beyond myeloid cells.

   Evidence Myo1f KO mouse, flow cytometry, in vitro migration, immunofluorescence for receptor polarization

   PMID:37207213

   Open questions at the time

   • Molecular mechanism linking MYO1F to receptor polarization machinery was not identified
   • Whether the αTAT1 scaffold mechanism operates in γδT cells was not tested
7. 2024 High

   Two studies defined the kinase-scaffold-acetyltransferase paradigm in new contexts: SYK phosphorylates MYO1F to recruit KAT2A for cGAS acetylation and type I IFN production during viral infection, while LCK phosphorylates MYO1F to facilitate αTAT1-mediated GAPDH acetylation enhancing glycolysis in T cells—generalizing MYO1F as a phosphorylation-activated acetyltransferase scaffold.

   Evidence Co-IP, mutagenesis of phospho-sites and acetylation sites, in vitro kinase assays, KO macrophages and T-cell-specific KO mice, GAPDH activity/Seahorse assays, human PTCL patient validation

   PMID:39668163 PMID:39694035

   Open questions at the time

   • Whether MYO1F recruits yet additional acetyltransferases to other substrates is unknown
   • How phosphorylation conformationally enables acetyltransferase binding is structurally unresolved
   • The oncogenic VAV1-MYO1F fusion's precise structural mechanism for hyperacetylation was not determined
8. 2025 High

   Proximity proteomics and mutagenesis identified MYO1F's SH3 domain as the hub for a multivalent CASS adaptor complex (CD2AP, ASAP1, SH3BP2, SH3KBP1) and its PH domain as essential for membrane targeting, together mediating localization to podosomes and phagocytic cups in macrophages—providing the structural logic for MYO1F recruitment.

   Evidence BioID proximity labeling, SH3/PH domain mutagenesis, Co-IP, immunofluorescence, phagocytosis assays in macrophages and microglia (J Cell Sci)

   PMID:41208482

   Open questions at the time

   • Quantitative affinities for individual SH3-PRM interactions were not measured
   • Whether the CASS complex is required for the acetyltransferase scaffold functions is untested
9. 2025 Medium

   In tumor-associated neutrophils, TGF-β1 suppresses MYO1F transcription through SPI1 displacement via DNA methylation at intron 8, and MYO1F loss derepresses STAT3-dependent immunosuppression, revealing an epigenetic axis by which tumors exploit MYO1F downregulation.

   Evidence ChIP, bisulfite sequencing, MYO1F KO mice, TGF-β1 treatment, STAT3 inhibition, tumor models (J Exp Med)

   PMID:40202509

   Open questions at the time

   • Direct mechanism by which MYO1F restrains STAT3 activity was not identified
   • Whether the acetyltransferase scaffold function mediates STAT3 regulation is unknown
10. 2026 Medium

    MYO1F was shown to recruit EPLINα to stabilize F-actin, reducing G-actin availability and enabling MRTFA nuclear translocation that transcriptionally upregulates integrin β2 (ITGB2), providing a direct mechanistic link from MYO1F's actin-binding functions to integrin expression and monocyte-endothelial adhesion in atherosclerosis.

    Evidence Co-IP-MS, Myo1f KO/Apoe−/− atherosclerosis mouse model, bone marrow transplant, actin polymerization assays, MRTFA nuclear fractionation, MRTFA inhibitor (Redox Biol)

    PMID:41610517

    Open questions at the time

    • Whether EPLINα recruitment requires MYO1F motor activity or the tail domains was not dissected
    • Relationship between the EPLINα–MRTFA pathway and the αTAT1 acetyltransferase scaffold function is unexplored

• Key unresolved questions include: (1) how phosphorylation-induced conformational changes in MYO1F enable acetyltransferase recruitment, (2) whether the CASS adaptor complex and the acetyltransferase scaffold functions are interdependent or parallel, (3) the structural basis for MYO1F's selectivity among acetyltransferases (αTAT1 vs. KAT2A) and substrates, and (4) how MYO1F motor activity versus scaffold activity are coordinated in vivo.
• No high-resolution structure of MYO1F tail domains in complex with partners
• No reconstituted system testing motor-scaffold coupling
• Functional redundancy with MYO1E at podosomes not fully resolved