JMY

JMY is a multifunctional actin nucleation factor that integrates cytoskeletal remodeling with transcriptional regulation, autophagy, and apoptosis. It nucleates actin filaments by two mechanisms — direct Spire-like nucleation via tandem WH2 domains and Arp2/3 complex activation via its C-terminal WCA module — and its nucleocytoplasmic distribution is governed by actin monomer occupancy of a WH2/NLS overlap region that blocks importin binding when G-actin is bound (PMID:19287377, PMID:22262458). In the cytoplasm, JMY promotes cell migration, Golgi vesicular trafficking, oligodendrocyte morphogenesis, and LC3-mediated phagophore actin assembly during autophagy, while also driving Arp2/3-dependent mitochondrial permeabilization during DNA damage-induced apoptosis; additionally, JMY activates MRTF-A by competing with RPEL motifs for G-actin independently of its nucleation activity (PMID:30463620, PMID:33872315, PMID:30593260, PMID:25015719). In the nucleus, JMY functions as a p53 cofactor whose Arp2/3-dependent actin nucleation is required for transcriptional activation of DNA repair genes such as XPC and XRCC5, and its protein levels are controlled by Mdm2-mediated ubiquitin-dependent degradation and transcriptionally induced by HIF-1α under hypoxia (PMID:37142657, PMID:17170761, PMID:21625218).

1. 2006 High

   Establishing how JMY protein levels are controlled resolved a key regulatory question: Mdm2 directly targets JMY for ubiquitin-dependent degradation via its RING finger domain, independently of p53, explaining how DNA damage stabilizes JMY to augment p53 cofactor function.

   Evidence Ubiquitination assays, Mdm2 RING mutants, pharmacological Mdm2 inhibition, and immunoblotting in human cell lines

   PMID:17170761

   Open questions at the time

   • Identity of deubiquitinases that counteract Mdm2-mediated JMY turnover unknown
   • No structural basis for Mdm2-JMY recognition
2. 2009 High

   The discovery that JMY possesses dual actin nucleation activities — Arp2/3 activation via WCA and Spire-like nucleation via tandem WH2 domains — established it as the first protein combining both mechanisms, redefining JMY from a transcriptional cofactor to a cytoskeletal regulator of cell motility.

   Evidence In vitro pyrene-actin nucleation assays, Arp2/3 activation assays, RNAi and overexpression in HL-60 and adherent cells, live-cell migration imaging

   PMID:19287377

   Open questions at the time

   • Mechanism of autoinhibition of full-length JMY not resolved in this study
   • Relative contributions of Arp2/3-dependent versus Spire-like nucleation in vivo unclear
3. 2011 High

   Multiple studies collectively revealed JMY's functional breadth: autoinhibition suppresses full-length JMY's nucleation in cells, JMY is transcriptionally induced by HIF-1α to drive hypoxic migration, and JMY is required for asymmetric division in oocyte meiosis.

   Evidence In vitro nucleation and bead motility assays identifying autoinhibition (PMID:21965285); ChIP/reporter assays for HIF-1α at JMY promoter plus siRNA migration assays under hypoxia (PMID:21625218); RNAi and antibody injection in mouse oocytes with spindle migration phenotyping (PMID:21266449)

   PMID:21266449 PMID:21625218 PMID:21965285

   Open questions at the time

   • Mechanism by which autoinhibition is relieved in vivo unresolved
   • Whether HIF-1α-driven JMY induction uses the same nucleation mode as normoxic JMY unclear
   • Role of JMY's nuclear vs cytoplasmic pools in oocyte maturation not distinguished
4. 2012 High

   A key question — how does JMY switch between cytoplasmic and nuclear pools? — was answered by demonstrating that the WH2 domains overlap with the NLS, so G-actin binding occludes importin recognition; DNA damage-induced actin polymerization frees the NLS for importin-β-mediated nuclear import.

   Evidence WH2/NLS mutagenesis, importin binding assays, subcellular fractionation, live-cell imaging, pharmacological actin perturbation

   PMID:22262458

   Open questions at the time

   • Post-translational modifications that may further regulate nuclear import not identified
   • Kinetics of NLS exposure in living cells not quantified
5. 2014 Medium

   Extending JMY's cytoplasmic roles beyond migration, JMY was shown to localize to vesiculo-tubular structures and interact with VAP-A, with overexpression dispersing the Golgi and impairing VSV-G anterograde transport, implicating JMY in actin-dependent vesicular trafficking at the trans-Golgi network.

   Evidence Mass spectrometry interactome, co-immunoprecipitation of VAP-A, immunofluorescence co-localization, VSV-G transport assay

   PMID:25015719

   Open questions at the time

   • Overexpression-based phenotype; loss-of-function confirmation for trafficking role lacking
   • Whether JMY-VAP-A interaction is direct or mediated by a bridging factor not resolved
6. 2018 High

   Two studies expanded JMY's functional repertoire: JMY activates MRTF-A by competing with RPEL motifs for G-actin in a nucleation-independent manner, and JMY is required for oligodendrocyte morphogenesis and myelination through actin-dependent protrusion dynamics.

   Evidence Recombinant actin competition assays, Arp2/3 inhibitor/knockdown confirming nucleation-independence, luciferase reporter for MRTF-A (PMID:30463620); RNAi in oligodendrocytes with live morphodynamics and neuron co-culture myelination assays (PMID:29732611)

   PMID:29732611 PMID:30463620

   Open questions at the time

   • Physiological relevance of JMY-MRTF-A axis in vivo not tested
   • Whether JMY's role in myelination requires nuclear or cytoplasmic activity undetermined
7. 2019 High

   JMY's role in autophagy was mechanistically defined: membrane-bound LC3 directly recruits JMY to phagophores and stimulates its actin nucleation activity, while TTC5/STRAP antagonizes this recruitment, establishing a regulated actin-dependent step in autophagosome formation.

   Evidence In vitro reconstitution with LC3-decorated membranes, co-immunoprecipitation, cellular autophagy flux assays

   PMID:30593260

   Open questions at the time

   • Whether JMY's Spire-like or Arp2/3-dependent nucleation mode predominates at the phagophore unresolved
   • In vivo autophagy phenotype in JMY knockout animals not reported
8. 2020 Medium

   Conditional knockout studies in mice demonstrated JMY's in vivo requirement: Sertoli cell-specific Jmy deletion impaired blood-testis barrier integrity, spermatid adhesion, and male fertility, with JMY interacting with α-actinin1 and SORBS2 to organize junctional actin; separately, irradiated glioblastoma stem cells use the HIF-1α→JMY pathway for radiation-induced migration.

   Evidence Sertoli cell-specific Jmy conditional knockout with sperm/BTB analysis and co-IP of partners (PMID:32279424); siRNA of JMY/HIF-1α in irradiated GSCs with migration and localization assays (PMID:33128011)

   PMID:32279424 PMID:33128011

   Open questions at the time

   • Mechanism linking JMY to BTB tight junction proteins not fully delineated
   • Whether JMY drives invasion or only migration in GSCs in vivo unknown
9. 2021 High

   A long-standing question about JMY's pro-apoptotic function was mechanistically resolved: JMY drives DNA damage-induced intrinsic apoptosis through Arp2/3-dependent actin assembly near mitochondria, promoting cytochrome c release and caspase activation, while JMY loss upregulates the survival factor RhoD.

   Evidence CRISPR and siRNA inactivation of WASP-family genes, caspase/cytochrome c assays, immunofluorescence of actin-cytochrome c co-territories, gene expression analysis

   PMID:33872315

   Open questions at the time

   • How Arp2/3-nucleated actin physically promotes mitochondrial outer membrane permeabilization is mechanistically unresolved
   • Direct interaction between JMY-nucleated actin filaments and mitochondria not demonstrated
10. 2023 High

    The nuclear function of JMY in DNA repair was mechanistically clarified: nuclear JMY uses Arp2/3-dependent actin nucleation to enable p53-dependent transcription of DNA repair genes (XPC, XRCC5, TP53I3), and JMY loss increases DNA damage accumulation and sensitizes cells to DDR kinase inhibitors.

    Evidence Transcriptomics, CRISPR knockout, siRNA, comet assay, domain mutant rescue, cell survival assays

    PMID:37142657

    Open questions at the time

    • How nuclear actin nucleation by JMY facilitates p53-dependent transcription at the chromatin level is unknown
    • Whether JMY nucleates actin at specific genomic loci or broadly in the nucleoplasm unresolved
11. 2025 Medium

    JMY was placed downstream of a PCSK9→LIN28A→HES5 axis controlling microfilament integrity in neural progenitors, with JMY overexpression worsening neural tube defects in zebrafish PCSK9-loss models.

    Evidence PCSK9 knockout ESC/neural organoid models, transcriptome sequencing, zebrafish JMY overexpression

    PMID:40788992

    Open questions at the time

    • Whether endogenous JMY levels are rate-limiting for neural tube closure in mammals untested
    • Direct transcriptional regulation of JMY by HES5 not demonstrated at the promoter level

• Critical open questions remain: what relieves JMY's autoinhibition in specific cellular contexts, what is the structural basis for autoinhibition, and how does nuclear actin nucleated by JMY mechanistically facilitate p53-dependent transcription at target gene loci.
• No crystal or cryo-EM structure of full-length JMY available
• Activating signals or co-factors that relieve autoinhibition in vivo not identified
• Functional separation of JMY's Spire-like vs Arp2/3-dependent activities in specific biological contexts incomplete