MYOF

MYOF (myoferlin) is a membrane-associated protein implicated in vesicle trafficking and tissue homeostasis whose loss of function causes human disease and whose levels and isoforms are tightly controlled in cancer and infection contexts (PMID:31297131, PMID:39934162). A truncating frameshift variant in MYOF causes limb-girdle muscular dystrophy with cardiomyopathy, with the disease-causative role of MYOF loss-of-function confirmed in patient-derived skeletal muscle mesenchymal progenitor cells and zebrafish modeling (PMID:31297131). In cancer, MYOF acts as a scaffold that recruits the deubiquitinase OTUB1 together with ILF3, preventing K48-linked ubiquitination and proteasomal degradation of ILF3; stabilized ILF3 binds and stabilizes LCN2 mRNA, promoting LCN2 expression and suppressing ferroptosis in pancreatic cancer cells (PMID:40381229). MYOF protein abundance is itself constrained by the E3 ubiquitin ligase TRIM8, which directs K48-linked polyubiquitination and proteasomal degradation of MYOF, thereby restraining MMP secretion and tumor cell migration and invasion (PMID:39934162). MYOF isoform composition is set by hnRNPLL-regulated alternative splicing, where hnRNPLL promotes inclusion that generates the pro-migratory short isoform MYOFb (PMID:39742990). During RNA virus infection, MYOF associates with influenza viral ribonucleoprotein complexes and colocalizes with Rab11a endosomal recycling vesicles, a role conserved across RSV and Sendai virus [PMID:bio_10.1101_2024.07.02.601679].

1. 2019 Medium

   Established that MYOF loss-of-function is causative for human muscle and cardiac disease, moving MYOF from a candidate to a confirmed disease gene.

   Evidence Whole exome sequencing of a frameshift variant, RNA-seq and morphology in patient-derived muscle progenitor cells, and zebrafish phenotype modeling

   PMID:31297131

   Open questions at the time

   • The molecular pathway connecting MYOF loss to dystrophic and cardiac phenotypes is not defined
   • Single family/variant; allelic spectrum not established
   • No mechanistic link to membrane repair or trafficking demonstrated in this study
2. 2024 Medium

   Identified hnRNPLL-driven alternative splicing as the upstream switch generating the pro-migratory MYOFb isoform, explaining how MYOF isoform choice contributes to metastatic behavior.

   Evidence hnRNPLL knockdown with exon-skipping RNA-seq plus hnRNPLL and MYOFb overexpression with migration/invasion assays in pancreatic cancer cells

   PMID:39742990

   Open questions at the time

   • Functional distinction between MYOFb and the full-length isoform at the protein level is not resolved
   • Direct binding of hnRNPLL to MYOF pre-mRNA not shown
   • Whether isoform switching operates outside pancreatic cancer is untested
3. 2024 Medium

   Placed MYOF in viral RNA trafficking by showing it associates with viral ribonucleoprotein complexes and Rab11a recycling vesicles, suggesting a conserved role in RNA virus assembly/egress.

   Evidence Co-localization imaging, biochemical association, and loss-of-function in IAV, RSV, and SeV infection models (preprint)

   PMID:bio_10.1101_2024.07.02.601679

   Open questions at the time

   • Preprint, single lab, not peer-reviewed
   • Proposed EHD recruitment to vRNP vesicles not directly demonstrated
   • Mechanism of MYOF recruitment to vRNP/Rab11a vesicles unresolved
4. 2025 Medium

   Defined a MYOF scaffolding function that stabilizes ILF3 via OTUB1 to sustain LCN2 expression and suppress ferroptosis, providing a molecular pathway for MYOF in tumor cell survival.

   Evidence MYOF knockout in vitro and in xenografts, co-immunoprecipitation, proteasome inhibitor assays, and ectopic LCN2 rescue in pancreatic cancer cells

   PMID:40381229

   Open questions at the time

   • Structural basis of the MYOF–OTUB1–ILF3 ternary complex not determined
   • Whether this scaffolding activity relates to MYOF's trafficking/membrane functions is unknown
   • Direct vs indirect nature of the interactions rests on Co-IP without reciprocal structural validation
5. 2025 Medium

   Showed MYOF protein levels are controlled by TRIM8-mediated K48 polyubiquitination and degradation, identifying a post-translational brake on MYOF-driven MMP secretion and invasion.

   Evidence Gain/loss-of-function and MYOF rescue in NSCLC cells, ubiquitination assays, and xenograft model

   PMID:39934162

   Open questions at the time

   • TRIM8 ubiquitination site(s) on MYOF not mapped
   • How MMP secretion is mechanistically linked to MYOF is not detailed
   • Whether TRIM8 regulation applies to MYOF's muscle functions is untested

• How MYOF's vesicle-trafficking/membrane biology mechanistically unifies its disparate roles in muscle disease, cancer scaffolding, and viral RNA transport remains unresolved.
• No single mechanistic study connects the membrane/trafficking function to the cancer scaffolding role
• No structural model of MYOF or its complexes in the corpus
• Tissue-specific determinants of MYOF function not characterized