Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9
Due to their low pathogenicity, immunogenicity, and long-term gene expression, adeno-associated virus (AAV) vectors emerged as safe and efficient gene delivery tools, over-coming setbacks experienced with other viral gene delivery systems in early gene therapy trials. Among AAVs, AAV9 can translocat...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/3141 |
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| author | Anett Hudák Matthew Roach Dávid Pusztai Aladár Pettkó-Szandtner Annamária Letoha László Szilák Mimoun Azzouz Tamás Letoha |
| author_facet | Anett Hudák Matthew Roach Dávid Pusztai Aladár Pettkó-Szandtner Annamária Letoha László Szilák Mimoun Azzouz Tamás Letoha |
| author_sort | Anett Hudák |
| collection | DOAJ |
| description | Due to their low pathogenicity, immunogenicity, and long-term gene expression, adeno-associated virus (AAV) vectors emerged as safe and efficient gene delivery tools, over-coming setbacks experienced with other viral gene delivery systems in early gene therapy trials. Among AAVs, AAV9 can translocate through the blood-brain barrier (BBB), making it a promising gene delivery tool for transducing the central nervous system (CNS) via systemic administration. Recent reports on the shortcomings of AAV9-mediated gene delivery into the CNS require reviewing the molecular base of AAV9 cellular biology. A more detailed understanding of AAV9’s cellular entry would eradicate current hurdles and enable more efficient AAV9-based gene therapy approaches. Syndecans, the transmembrane family of heparan-sulfate proteoglycans, facilitate the cellular uptake of various viruses and drug delivery systems. Utilizing human cell lines and syndecan-specific cellular assays, we assessed the involvement of syndecans in AAV9’s cellular entry. The ubiquitously expressed isoform, syndecan-4 proved its superiority in facilitating AAV9 internalization among syndecans. Introducing syndecan-4 into poorly transducible cell lines enabled robust AAV9-dependent gene transduction, while its knockdown reduced AAV9’s cellular entry. Attachment of AAV9 to syndecan-4 is mediated not just by the polyanionic heparan-sulfate chains but also by the cell-binding domain of the extracellular syndecan-4 core protein. Co-immunoprecipitation assays and affinity proteomics also confirmed the role of syndecan-4 in the cellular entry of AAV9. Overall, our findings highlight the universally expressed syndecan-4 as a significant contributor to the cellular internalization of AAV9 and provide a molecular-based, rational explanation for the low gene delivery potential of AAV9 into the CNS. |
| first_indexed | 2024-03-11T08:44:22Z |
| format | Article |
| id | doaj.art-c818125232fa4362a1426589980c8917 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:44:22Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c818125232fa4362a1426589980c89172023-11-16T20:55:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244314110.3390/ijms24043141Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9Anett Hudák0Matthew Roach1Dávid Pusztai2Aladár Pettkó-Szandtner3Annamária Letoha4László Szilák5Mimoun Azzouz6Tamás Letoha7Pharmacoidea Ltd., H-6726 Szeged, HungaryDepartment of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UKPharmacoidea Ltd., H-6726 Szeged, HungaryBiological Research Centre, Institute of Plant Biology, H-6726 Szeged, HungaryAlbert Szent-Györgyi Clinical Center, Department of Medicine, Faculty of Medicine, University of Szeged, H-6726 Szeged, HungarySzilák Laboratories Ltd., H-6725 Szeged, HungaryDepartment of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UKPharmacoidea Ltd., H-6726 Szeged, HungaryDue to their low pathogenicity, immunogenicity, and long-term gene expression, adeno-associated virus (AAV) vectors emerged as safe and efficient gene delivery tools, over-coming setbacks experienced with other viral gene delivery systems in early gene therapy trials. Among AAVs, AAV9 can translocate through the blood-brain barrier (BBB), making it a promising gene delivery tool for transducing the central nervous system (CNS) via systemic administration. Recent reports on the shortcomings of AAV9-mediated gene delivery into the CNS require reviewing the molecular base of AAV9 cellular biology. A more detailed understanding of AAV9’s cellular entry would eradicate current hurdles and enable more efficient AAV9-based gene therapy approaches. Syndecans, the transmembrane family of heparan-sulfate proteoglycans, facilitate the cellular uptake of various viruses and drug delivery systems. Utilizing human cell lines and syndecan-specific cellular assays, we assessed the involvement of syndecans in AAV9’s cellular entry. The ubiquitously expressed isoform, syndecan-4 proved its superiority in facilitating AAV9 internalization among syndecans. Introducing syndecan-4 into poorly transducible cell lines enabled robust AAV9-dependent gene transduction, while its knockdown reduced AAV9’s cellular entry. Attachment of AAV9 to syndecan-4 is mediated not just by the polyanionic heparan-sulfate chains but also by the cell-binding domain of the extracellular syndecan-4 core protein. Co-immunoprecipitation assays and affinity proteomics also confirmed the role of syndecan-4 in the cellular entry of AAV9. Overall, our findings highlight the universally expressed syndecan-4 as a significant contributor to the cellular internalization of AAV9 and provide a molecular-based, rational explanation for the low gene delivery potential of AAV9 into the CNS.https://www.mdpi.com/1422-0067/24/4/3141AAV9cellular entrygene deliveryheparan sulfate proteoglycanssyndecans |
| spellingShingle | Anett Hudák Matthew Roach Dávid Pusztai Aladár Pettkó-Szandtner Annamária Letoha László Szilák Mimoun Azzouz Tamás Letoha Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9 International Journal of Molecular Sciences AAV9 cellular entry gene delivery heparan sulfate proteoglycans syndecans |
| title | Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9 |
| title_full | Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9 |
| title_fullStr | Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9 |
| title_full_unstemmed | Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9 |
| title_short | Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9 |
| title_sort | syndecan 4 mediates the cellular entry of adeno associated virus 9 |
| topic | AAV9 cellular entry gene delivery heparan sulfate proteoglycans syndecans |
| url | https://www.mdpi.com/1422-0067/24/4/3141 |
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