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Here, we identify microtubule detyrosination \u2013 a microtubule post-translational modification \u2013 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 GSK3\u03b2\u2013CLASP2 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.<\/jats:p>","DOI":"10.1242\/jcs.264190","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T09:05:31Z","timestamp":1761555931000},"source":"Crossref","is-referenced-by-count":3,"title":["Suppressing microtubule detyrosination augments adeno-associated virus 2 endosomal escape and gene delivery"],"prefix":"10.1242","volume":"138","author":[{"given":"Shefali","family":"Tripathi","sequence":"first","affiliation":[{"name":"Indian Institute of Technology Kanpur 1 Dept of Biological Sciences and Bioengineering , , Kanpur 208016 ,","place":["India"]},{"name":"Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur 2 , Kanpur 208016 ,","place":["India"]},{"name":"Laurus Centre for Gene Therapy, Indian Institute of Technology Kanpur 3 , Kanpur 208016 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamshul","family":"Huda","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology Kanpur 1 Dept of Biological Sciences and Bioengineering , , Kanpur 208016 ,","place":["India"]},{"name":"Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur 2 , Kanpur 208016 ,","place":["India"]},{"name":"Laurus Centre for Gene Therapy, Indian Institute of Technology Kanpur 3 , Kanpur 208016 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joydipta","family":"Kar","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology Kanpur 1 Dept of Biological Sciences and Bioengineering , , Kanpur 208016 ,","place":["India"]},{"name":"Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur 2 , Kanpur 208016 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Chandra","sequence":"additional","affiliation":[{"name":"Sanjay Gandhi Post Graduate Institute of Medical Sciences 4 Dept of Hematology , , Lucknow 226014 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giridhara R.","family":"Jayandharan","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology Kanpur 1 Dept of Biological Sciences and Bioengineering , , Kanpur 208016 ,","place":["India"]},{"name":"Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur 2 , Kanpur 208016 ,","place":["India"]},{"name":"Laurus Centre for Gene Therapy, Indian Institute of Technology Kanpur 3 , Kanpur 208016 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5168-1462","authenticated-orcid":false,"given":"Nitin","family":"Mohan","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology Kanpur 1 Dept of Biological Sciences and Bioengineering , , Kanpur 208016 ,","place":["India"]},{"name":"Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur 2 , Kanpur 208016 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"2025120505585894000_JCS264190C1","doi-asserted-by":"publisher","first-page":"1448","DOI":"10.1126\/science.aao4165","article-title":"Vasohibins\/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation","volume":"358","author":"Aillaud","year":"2017","journal-title":"Science"},{"key":"2025120505585894000_JCS264190C2","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1089\/hgtb.2011.034","article-title":"Universal real-time PCR for the detection and quantification of adeno-associated virus serotype 2-derived inverted terminal repeat sequences","volume":"23","author":"Aurnhammer","year":"2012","journal-title":"Hum. 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