{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Xiao PJ"],"funding":["NIDDK NIH HHS","NIAID NIH HHS","NHLBI NIH HHS","NCI NIH HHS","NIAMS NIH HHS"],"pagination":["309-24"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4841008"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["27(4)"],"pubmed_abstract":["Perinuclear retention of viral particles is a poorly understood phenomenon observed during many virus infections. In this study, we investigated whether perinuclear accumulation acts as a barrier to limit recombinant adeno-associated virus (rAAV) transduction. After nocodazole treatment to disrupt microtubules at microtubule-organization center (MT-MTOC) after virus entry, we observed higher rAAV transduction. To elucidate the role of MT-MTOC in rAAV infection and study its underlying mechanisms, we demonstrated that rAAV's perinuclear localization was retained by MT-MTOC with fluorescent analysis, and enhanced rAAV transduction from MT-MTOC disruption was dependent on the rAAV capsid's nuclear import signals. Interestingly, after knocking down RhoA or inhibiting its downstream effectors (ROCK and Actin), MT-MTOC disruption failed to increase rAAV transduction or nuclear entry. These data suggest that enhancement of rAAV transduction is the result of increased trafficking to the nucleus via the RhoA-ROCK-Actin pathway. Ten-fold higher rAAV transduction was also observed by disrupting MT-MTOC in brain, liver, and tumor in vivo. In summary, this study indicates that virus perinuclear accumulation at MT-MTOC is a barrier-limiting parameter for effective rAAV transduction and defines a novel defense mechanism by which host cells restrain viral invasion."],"journal":["Human gene therapy"],"pubmed_title":["Disruption of Microtubules Post-Virus Entry Enhances Adeno-Associated Virus Vector Transduction."],"pmcid":["PMC4841008"],"funding_grant_id":["P30 CA016086","R01 AI072176","R01DK084033","R01AR064369","P01HL112761","R01AI072176"],"pubmed_authors":["Xiao PJ","Mitchell AM","Li C","Samulski RJ","Huang L"],"additional_accession":[]},"is_claimable":false,"name":"Disruption of Microtubules Post-Virus Entry Enhances Adeno-Associated Virus Vector Transduction.","description":"Perinuclear retention of viral particles is a poorly understood phenomenon observed during many virus infections. In this study, we investigated whether perinuclear accumulation acts as a barrier to limit recombinant adeno-associated virus (rAAV) transduction. After nocodazole treatment to disrupt microtubules at microtubule-organization center (MT-MTOC) after virus entry, we observed higher rAAV transduction. To elucidate the role of MT-MTOC in rAAV infection and study its underlying mechanisms, we demonstrated that rAAV's perinuclear localization was retained by MT-MTOC with fluorescent analysis, and enhanced rAAV transduction from MT-MTOC disruption was dependent on the rAAV capsid's nuclear import signals. Interestingly, after knocking down RhoA or inhibiting its downstream effectors (ROCK and Actin), MT-MTOC disruption failed to increase rAAV transduction or nuclear entry. These data suggest that enhancement of rAAV transduction is the result of increased trafficking to the nucleus via the RhoA-ROCK-Actin pathway. Ten-fold higher rAAV transduction was also observed by disrupting MT-MTOC in brain, liver, and tumor in vivo. In summary, this study indicates that virus perinuclear accumulation at MT-MTOC is a barrier-limiting parameter for effective rAAV transduction and defines a novel defense mechanism by which host cells restrain viral invasion.","dates":{"release":"2016-01-01T00:00:00Z","publication":"2016 Apr","modification":"2025-04-19T11:54:48.339Z","creation":"2019-03-27T02:12:11Z"},"accession":"S-EPMC4841008","cross_references":{"pubmed":["26942476"],"doi":["10.1089/hum.2016.008"]}}