Endocytosis and Nuclear Trafficking of Adeno-Associated Virus Type 2 Are Controlled by Rac1 and Phosphatidylinositol-3 Kinase Activation
| Autor: | Jusan Yang, Peter K. Benson, John F. Engelhardt, Salih Sanlioglu, E. Morrey Atkinson, Thomas C. Reynolds |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
rac1 GTP-Binding Protein
viruses Immunology Endocytic cycle Biology Virus Replication MAP3K7 Endocytosis Microbiology MAP2K7 Phosphatidylinositol 3-Kinases Virology Humans ASK1 Cyclin-dependent kinase 2 Biological Transport Dependovirus Protein kinase R Molecular biology Virus-Cell Interactions Cell biology Insect Science biology.protein Cyclin-dependent kinase 9 HeLa Cells Signal Transduction |
| Zdroj: | Journal of Virology. 74:9184-9196 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.74.19.9184-9196.2000 |
| Popis: | Adeno-associated virus (AAV) is a single-stranded DNA parvovirus that causes no currently known pathology in humans. Despite the fact that this virus is of increasing interest to molecular medicine as a vector for gene delivery, relatively little is known about the cellular mechanisms controlling infection. In this study, we have examined endocytic and intracellular trafficking of AAV-2 using fluorescent (Cy3)-conjugated viral particles and molecular techniques. Our results demonstrate that internalization of heparan sulfate proteoglycan-bound AAV-2 requires αVβ5 integrin and activation of the small GTP-binding protein Rac1. Following endocytosis, activation of a phosphatidylinositol-3 (PI3) kinase pathway was necessary to initiate intracellular movement of AAV-2 to the nucleus via both microfilaments and microtubules. Inhibition of Rac1 using a dominant N17Rac1 mutant led to a decrease in AAV-2-mediated PI3 kinase activation, indicating that Rac1 may act proximal to PI3 kinase during AAV-2 infection. In summary, our results indicate that αVβ5 integrin-mediated endocytosis of AAV-2 occurs through a Rac1 and PI3 kinase activation cascade, which directs viral movement along the cytoskeletal network to the nucleus. |
| Databáze: | OpenAIRE |
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