ArticleJournal of cell science2025
Suppressing microtubule detyrosination augments adeno-associated virus 2 endosomal escape and gene delivery.
Article in Journal of cell science, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
1 citing paper in PubMed.
- LC3 forms functional nanoclusters on autophagosomes.EMBO reports · 2026Article
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6 authors.
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Abstract
Adeno-associated virus (AAV) is a widely used vector for gene delivery, yet the host intracellular trafficking barriers often limit its therapeutic efficacy. Here, we identify microtubule detyrosination - a microtubule post-translational modification - as a key regulator of AAV2 endo-lysosomal processing. Using super-resolution microscopy (SIM/STORM), we show that upon AAV2 endocytosis, the host upregulates microtubule detyrosination via the GSK3β-CLASP2 signaling axis. Single-particle tracking of recombinant virus reveals that detyrosinated microtubules form a physical and functional barrier, restricting AAV2 motility and promoting lysosomal trapping. Restoring microtubule tyrosination via tubulin-tyrosine ligase overexpression or pharmacological inhibition of detyrosination with parthenolide, enhances endosomal escape and perinuclear accumulation of AAV2, translating to improved gene delivery in host cells. Notably, a clinically relevant pro-drug of parthenolide (DMAPT) also displayed a similar trend of enhancing AAV2-driven coagulation factor IX expression in hemophilia B mouse models. Our findings uncover a host mechanism that reshapes the microtubule landscape to restrict AAV2 trafficking and identify microtubule detyrosination as a novel druggable target to improve AAV-based gene therapy.
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