Affinage

MYOF

Myoferlin · UniProt Q9NZM1

Round 2 corrected
Length
2061 aa
Mass
234.7 kDa
Annotated
2026-04-29
42 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Myoferlin (MYOF) is a multi-C2-domain, type II transmembrane protein that mediates calcium-dependent membrane fusion, vesicle trafficking, and membrane repair, with particular importance in muscle and in cancer cell membrane dynamics. Its C2A domain binds phosphatidylserine in a calcium-sensitive manner, and MYOF is expressed most highly in prefusion myoblasts, distinguishing it temporally from the related protein dysferlin (PMID:11959863). Loss-of-function mutations in MYOF cause combined cardiomyopathy and limb-girdle muscular dystrophy in humans, confirmed by zebrafish phenocopy (PMID:31297131). In pancreatic and lung cancers, MYOF promotes progression by recruiting the deubiquitinase OTUB1 to stabilize ILF3, which in turn stabilizes LCN2 mRNA and suppresses ferroptosis (PMID:40381229), while MYOF protein levels are themselves controlled by TRIM8-mediated K48-linked ubiquitination and proteasomal degradation, which limits MMP secretion and metastasis (PMID:39934162).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2000 Medium

    Identification of MYOF as a dysferlin-homologous, multi-C2-domain protein at the plasma and nuclear membranes of muscle cells established a new candidate for calcium-dependent membrane fusion in striated muscle.

    Evidence Database homology search and immunostaining in cardiac/skeletal muscle including mdx mouse

    PMID:10607832

    Open questions at the time
    • No direct functional assay for membrane fusion activity
    • Expression pattern characterized only in muscle; non-muscle roles unknown
  2. 2002 High

    Demonstrating that the C2A domain binds phosphatidylserine in a calcium-titratable fashion, and that a disease-relevant mutation disrupts this binding, provided the first mechanistic link between MYOF's C2 domains and lipid-membrane interaction required for its fusogenic role.

    Evidence In vitro phospholipid binding assay with calcium titration and site-directed mutagenesis of C2A domain

    PMID:11959863

    Open questions at the time
    • Only C2A tested; functional contributions of other C2 domains (C2B–C2F) uncharacterized
    • No in vivo membrane fusion assay performed
  3. 2019 Medium

    Discovery of a truncating MYOF variant in a patient with cardiomyopathy and limb-girdle muscular dystrophy, supported by zebrafish phenocopy, established MYOF as a bona fide human disease gene for combined skeletal–cardiac myopathy.

    Evidence Whole exome sequencing, RNA-seq of patient primary cells, zebrafish knockdown phenotyping

    PMID:31297131

    Open questions at the time
    • Single family reported; genetic spectrum and prevalence unknown
    • Precise cellular mechanism of muscle degeneration not delineated
  4. 2024 Medium

    Identification of hnRNPLL-regulated alternative splicing of MYOF exon 17 revealed that the short isoform MYOFb is the functionally pro-metastatic species in pancreatic cancer, adding an RNA-level regulatory layer to MYOF biology.

    Evidence RNA-seq after hnRNPLL knockdown, splicing reporters, isoform-specific overexpression/knockdown with migration and invasion assays

    PMID:39742990

    Open questions at the time
    • Structural or functional difference between isoforms at the protein level not defined
    • Relevance of isoform switching in non-cancer contexts unknown
  5. 2024 Medium

    Showing that MYOF associates with Rab11a-positive vRNP vesicles during influenza A infection and recruits EHD proteins expanded MYOF's vesicle trafficking role to viral egress, conserved across multiple RNA viruses.

    Evidence Co-immunoprecipitation with vRNPs, Rab11a colocalization imaging, knockdown across IAV/RSV/SeV (preprint)

    PMID:bio_10.1101_2024.07.02.601679

    Open questions at the time
    • Preprint; not yet peer-reviewed
    • Mechanism by which MYOF recruits EHD proteins not resolved at the domain level
    • Whether MYOF's role in viral egress is linked to its membrane repair function is untested
  6. 2025 High

    Elucidation of a MYOF–OTUB1–ILF3 axis in pancreatic cancer revealed that MYOF acts as a scaffold recruiting the deubiquitinase OTUB1 to stabilize ILF3, which in turn stabilizes LCN2 mRNA and suppresses ferroptosis — providing a direct oncogenic mechanism beyond membrane dynamics.

    Evidence Reciprocal Co-IP, K48-ubiquitination assays, mRNA stability assays, MYOF knockout with LCN2 epistasis rescue, in vivo xenograft

    PMID:40381229

    Open questions at the time
    • Which MYOF domain mediates OTUB1 and ILF3 recruitment is unknown
    • Whether this scaffolding function operates outside pancreatic cancer is untested
  7. 2025 High

    Demonstration that TRIM8 targets MYOF for K48-linked ubiquitination and proteasomal degradation, thereby suppressing MMP secretion and metastasis, established the first defined E3 ligase-mediated regulatory mechanism controlling MYOF protein turnover.

    Evidence K48-linkage-specific ubiquitination assays, TRIM8 gain/loss-of-function, MYOF rescue in TRIM8-overexpressing NSCLC cells, xenograft model, MMP secretion assays

    PMID:39934162

    Open questions at the time
    • TRIM8 recognition motif on MYOF not mapped
    • Whether TRIM8 regulation of MYOF operates in muscle or non-cancer contexts is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for MYOF's multi-C2-domain architecture in membrane fusion, the precise domain requirements for its scaffolding of OTUB1/ILF3 and EHD recruitment, and whether its muscle and cancer functions share a common vesicle-trafficking mechanism remain unresolved.
  • No high-resolution structure of full-length MYOF or individual C2 domains beyond C2A
  • Functional contributions of C2B–C2F domains are largely uncharacterized
  • Integration of membrane repair, vesicle trafficking, and scaffolding functions into a unified model is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 1 GO:0060090 molecular adaptor activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005634 nucleus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1643685 Disease 2 R-HSA-5653656 Vesicle-mediated transport 2 GO:0031410 cytoplasmic vesicle 1
Partners
HNRNPLLILF3OTUB1RAB11ATRIM8

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Myoferlin (MYOF) was identified as a protein highly homologous to dysferlin, associated with the plasma membrane and nuclear membrane in cardiac and skeletal muscle. It contains multiple C2 domains implicated in calcium-mediated membrane fusion events. Myoferlin expression was found to be upregulated at the membrane in mdx mouse skeletal muscle undergoing repeated degeneration/regeneration cycles, suggesting a role in membrane repair or maintenance. Database searching, antibody-based subcellular localization (plasma membrane and nuclear membrane association), immunostaining of mdx mouse muscle Human molecular genetics Medium 10607832
2002 The C2A domain of myoferlin (and dysferlin) binds phosphatidylserine in a calcium-sensitive manner. Phospholipid binding by C2A was regulated by calcium concentration, and a dysferlin muscular dystrophy point mutation engineered into C2A reduced calcium-sensitive phospholipid binding. Myoferlin is highly expressed in elongated 'prefusion' myoblasts and is decreased in mature myotubes, whereas dysferlin expression is greatest in mature myotubes, indicating distinct temporal roles in muscle development. In vitro phospholipid binding assay with calcium titration; site-directed mutagenesis of C2A domain; cell culture model of muscle differentiation with immunostaining The Journal of biological chemistry High 11959863
2019 A truncating frameshift variant in human MYOF (c.[2576delG; 2575G>C], p.G859QfsTer8) was identified in a patient with combined cardiomyopathy and limb-girdle muscular dystrophy. Functional studies in patient-derived primary skeletal muscle mesenchymal progenitor cells (RNA sequencing and morphological analysis) confirmed loss-of-function effects, and knockdown of MYOF in zebrafish recapitulated the muscle phenotype, establishing MYOF as causative for human muscle disease. Whole exome sequencing, RNA sequencing of patient primary cells, morphological analysis, zebrafish in vivo knockdown phenotyping Frontiers in genetics Medium 31297131
2020 Myoferlin (MYOF) is a type II transmembrane protein with a single C-terminal transmembrane domain involved in extracellular secretion, endocytosis, vesicle trafficking, membrane repair, membrane receptor recycling, and secreted protein efflux. Small molecule inhibitors targeting the MYOF C2D domain selectively inhibit cancer cell proliferation and migration, identifying C2D as a functional domain mediating MYOF's role in membrane transport processes. Review of published functional studies; small molecule inhibitor targeting C2D domain with cell proliferation and migration assays Current topics in medicinal chemistry Low 32552653
2024 Myoferlin associates with influenza A virus (IAV) viral ribonucleoprotein (vRNP) complexes in the cytoplasm during late-stage infection and colocalizes with Rab11a-containing vesicles. This role was conserved in vRNP trafficking of RSV and Sendai virus (SeV). Myoferlin likely recruits EHD family proteins (involved in endosomal biogenesis) to vRNP trafficking endosomes, indicating myoferlin acts as a host co-factor for Rab11a-dependent viral egress. Co-immunoprecipitation of myoferlin with vRNPs, colocalization imaging with Rab11a, functional knockdown experiments, conservation tested across multiple RNA viruses bioRxivpreprint Medium bio_10.1101_2024.07.02.601679
2024 hnRNPLL binds MYOF pre-mRNA and regulates alternative splicing of MYOF exon 17; hnRNPLL depletion causes exon 17 retention, reducing expression of the short MYOF isoform (MYOFb). Overexpression of hnRNPLL or MYOFb promotes pancreatic cancer cell migration and invasion, while hnRNPLL knockdown inhibits metastasis, establishing MYOFb as the functionally pro-metastatic isoform regulated by hnRNPLL-mediated splicing. RNA-seq after hnRNPLL knockdown, splicing reporter assays, isoform-specific overexpression and knockdown with migration/invasion assays Cancer letters Medium 39742990
2025 MYOF promotes PDAC progression by stabilizing ILF3 protein through recruiting OTUB1 deubiquitinase: MYOF physically recruits both OTUB1 and ILF3, enhancing their interaction and relieving K48-linked ubiquitination and proteasomal degradation of ILF3. Stabilized ILF3 in turn binds and stabilizes LCN2 mRNA, increasing LCN2 expression to suppress ferroptosis. MYOF knockout promotes ferroptosis via LCN2 downregulation, and ectopic LCN2 rescues the MYOF-KO phenotype. Co-immunoprecipitation of MYOF-OTUB1-ILF3 complex, ubiquitination assays, mRNA stability assays, MYOF knockout in vitro and in vivo xenograft, genetic epistasis (LCN2 rescue) Redox biology High 40381229
2025 TRIM8, an E3 ubiquitin ligase, targets MYOF for K48-linked polyubiquitination, leading to proteasome-mediated degradation of MYOF. TRIM8 overexpression reduced MYOF protein levels in NSCLC cells; restoring MYOF expression rescued cell migration in TRIM8-overexpressing cells. MYOF degradation by TRIM8 subsequently suppressed extracellular secretion of matrix metalloproteinases (MMPs), inhibiting lung cancer metastasis. Co-immunoprecipitation, K48-linked ubiquitination assays, gain- and loss-of-function experiments, MYOF rescue in TRIM8-overexpressing cells, xenograft in vivo model, MMP secretion assays Cell death & disease High 39934162

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2008 Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 787 18854154
2002 Directed proteomic analysis of the human nucleolus. Current biology : CB 780 11790298
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proceedings of the National Academy of Sciences of the United States of America 383 16009940
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2017 An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells. Cell 328 28388416
2012 Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 319 22810586
2016 Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. Cell reports 306 27342126
2022 CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1. Oncogene 259 36369321
2013 PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. Molecular cell 204 24332808
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2002 Calcium-sensitive phospholipid binding properties of normal and mutant ferlin C2 domains. The Journal of biological chemistry 168 11959863
2019 MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1. Gastroenterology 165 30711629
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2000 Myoferlin, a candidate gene and potential modifier of muscular dystrophy. Human molecular genetics 153 10607832
2013 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics 138 23533145
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2005 A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. American journal of human genetics 137 16385451
2003 Shared, unique and redundant functions of three members of the class I myosins (MyoA, MyoB and MyoF) in motility and chemotaxis in Dictyostelium. Journal of cell science 42 12953059
1995 Molecular genetic analysis of myoF, a new Dictyostelium myosin I gene. Biophysical journal 16 7787058
2021 Dynamics of the orphan myosin MyoF over Trypanosoma cruzi life cycle and along the endocytic pathway. Parasitology international 11 34464754
2019 Truncating Variant in Myof Gene Is Associated With Limb-Girdle Type Muscular Dystrophy and Cardiomyopathy. Frontiers in genetics 9 31297131
2020 An Emerging Therapeutic Approach by Targeting Myoferlin (MYOF) for Malignant Tumors. Current topics in medicinal chemistry 8 32552653
2025 Targeting MYOF suppresses pancreatic ductal adenocarcinoma progression by inhibiting ILF3-LCN2 signaling through disrupting OTUB1-mediated deubiquitination of ILF3. Redox biology 5 40381229
2024 hnRNPLL regulates MYOF alternative splicing and correlates with early metastasis in pancreatic ductal adenocarcinoma. Cancer letters 5 39742990
2025 E3 ligase TRIM8 suppresses lung cancer metastasis by targeting MYOF degradation through K48-linked polyubiquitination. Cell death & disease 2 39934162
2024 A missense variant in MYOF is associated with ARVC and sudden cardiac death. Gene 1 38253296
2023 Chronic systemic capillary leak syndrome with lymphatic capillaries involvement and MYOF mutation: case report and literature review. Frontiers in genetics 1 38054026
2025 In silico analysis of the oncogenic role of myoferlin (MYOF) and suggestion of folate as a potential therapeutic for brain cancer in the Caucasian population. Discover oncology 0 40665025
2024 Corrigendum: Chronic systemic capillary leak syndrome with lymphatic capillaries involvement and MYOF mutation: case report and literature review. Frontiers in genetics 0 39498317