Journal article
Directing Integrin-linked Endocytosis of Recombinant AAV Enhances Productive FAK-dependent Transduction
Molecular therapy, Vol.20(5), pp.972-983
05/2012
DOI: 10.1038/mt.2011.295
PMCID: PMC3345987
PMID: 22233580
Abstract
Recombinant adeno-associated virus (rAAV) is a widely used gene therapy vector. Although a wide range of rAAV serotypes can effectively enter most cell types, their transduction efficiencies (
i.e.
, transgene expression) can vary widely depending on the target cell type. Integrins play important roles as coreceptors for rAAV infection, however, it remains unclear how integrin-dependent and -independent mechanisms of rAAV endocytosis influence the efficiency of intracellular virus processing and ultimately transgene expression. In this study, we examined the contribution of integrin-mediated endocytosis to transduction of fibroblasts by rAAV2. Mn
++
-induced integrin activation significantly enhanced (~17-fold) the efficiency of rAAV2 transduction, without altering viral binding or endocytosis. rAAV2 subcellular localization studies demonstrated that Mn
++
promotes increased clustering of rAAV2 on integrins and recruitment of intracellular vinculin (an integrin effector) to sites of rAAV2 binding at the cell surface. Focal adhesion kinase (FAK), a downstream effector of integrin signals, was essential for rAAV2/integrin complex internalization and transduction. These findings support a model whereby integrin activation at the cell surface can redirect rAAV2 toward a FAK-dependent entry pathway that is more productive for cellular transduction. This pathway appears to be conserved for other rAAV serotypes that contain a capsid integrin-binding domain (AAV1 and AAV6).
Details
- Title: Subtitle
- Directing Integrin-linked Endocytosis of Recombinant AAV Enhances Productive FAK-dependent Transduction
- Creators
- Paul M Kaminsky - , Iowa City, IowaNicholas W Keiser - , Iowa City, IowaZiying Yan - , Iowa City, IowaDiana CM Lei-Butters - , Iowa City, IowaJohn F Engelhardt - , Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular therapy, Vol.20(5), pp.972-983
- DOI
- 10.1038/mt.2011.295
- PMID
- 22233580
- PMCID
- PMC3345987
- NLM abbreviation
- Mol Ther
- ISSN
- 1525-0016
- eISSN
- 1525-0024
- Publisher
- Nature Publishing Group
- Alternative title
- Mn++-dependent Integrin Activation Enhances rAAV Transduction
- Language
- English
- Date published
- 05/2012
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984025356202771
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