Suppressing microtubule detyrosination augments AAV2 endosomal escape and gene delivery.
Tripathi, S.; Huda, S.; Kar, J.; Chandra, D.; R Jayandharan, G.; Mohan, N.
Show abstract
Adeno-associated virus (AAV) is a widely used vector for gene delivery, yet the host intracellular trafficking barriers often limit its efficacy. Here, we identify microtubule detyrosination--a tubulin 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 GSK3{beta}-CLASP2 signaling axis. Single particle tracking of the 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--boosted AAV2 endosomal escape, perinuclear accumulation, and gene delivery in cells. Notably, a clinically relevant prodrug of parthenolide, DMAPT, also displayed a similar trend of enhanced AAV2-driven 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 AAV2-based gene therapies.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- The membrane associated accessory protein is an adeno-associated viral egress factor 97%
- An updated suite of viral vectors for in vivo calcium imaging using local and retro-orbital injections 95%
- Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates 95%
Similar papers in this journal
Similar papers in this journal
- The SARS-CoV-2 spike (S) and the orthoreovirus p15 cause neuronal and glial fusion 94%
- A Safe Harbor-Targeted CRISPR/Cas9 Homology Independent Targeted Integration (HITI) System for Multi-Modality Reporter Gene-Based Cell Tracking 93%
- In vivo mRNA delivery to virus-specific T cells by light-induced ligand exchange of MHC class I antigen-presenting nanoparticles 93%
Similar papers in this journal
- AAVs Targeting Human Carbonic Anhydrase IV Enhance Gene Delivery to the Brain 95%
- Fast retrograde access to projection neuron circuits underlying vocal learning in songbirds 94%
- Automated live-cell single-molecule tracking in enteroid monolayers reveals transcription factor dynamics probing lineage-determining function 94%
Similar papers in this journal
- An arginine-rich nuclear localization signal (ArgiNLS) strategy for streamlined image segmentation of single-cells 96%
- Adeno-associated viruses for efficient gene expression in the axolotl nervous system 94%
- Phosphatidylinositol 3-phosphate mediates Arc capsids secretion through the multivesicular body pathway 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.