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Cited by 126Virus-based gene therapy researchRNA Interference and Gene DeliveryViral Infectious Diseases and Gene Expression in Insects

Adeno-Associated Virus Type 2-Mediated Gene Transfer: Role of Cellular FKBP52 Protein in Transgene Expression

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Qing, Keyun, Hansen, Jonathan, Weigel-Kelley, Kirsten A., Tan, Mengqun, Zhou, Shangzhen, Srivastava, Arun·2001·Journal of Virology
DOI 10.1128/jvi.75.19.8968-8976.2001PMC PMC114465
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Abstract

Although adeno-associated virus type 2 (AAV) has gained attention as a potentially useful vector for human gene therapy, the transduction efficiencies of AAV vectors vary greatly in different cells and tissues in vitro and in vivo. We have documented that a cellular tyrosine phosphoprotein, designated the single-stranded D-sequence-binding protein (ssD-BP), plays a crucial role in AAV-mediated transgene expression (K. Y. Qing, X.-S. Wang, D. M. Kube, S. Ponnazhagan, A. Bajpai, and A. Srivastava, Proc. Natl. Acad. Sci. USA 94:10879–10884, 1997). We have documented a strong correlation between the phosphorylation state of ssD-BP and AAV transduction efficiency in vitro as well as in vivo (K. Y. Qing, B. Khuntrirat, C. Mah, D. M. Kube, X.-S. Wang, S. Ponnazhagan, S. Z. Zhou, V. J. Dwarki, M. C. Yoder, and A. Srivastava, J. Virol . 72:1593–1599, 1998). We have also established that the ssD-BP is phosphorylated by epidermal growth factor receptor protein tyrosine kinase and that the tyrosine-phosphorylated form, but not the dephosphorylated form, of ssD-BP prevents AAV second-strand DNA synthesis and, consequently, results in a significant inhibition of AAV-mediated transgene expression (C. Mah, K. Y. Qing, B. Khuntrirat, S. Ponnazhagan, X.-S. Wang, D. M. Kube, M. C. Yoder, and A. Srivastava, J. Virol . 72:9835–9841, 1998). Here, we report that a partial amino acid sequence of ssD-BP purified from HeLa cells is identical to a portion of a cellular protein that binds the immunosuppressant drug FK506, termed the FK506-binding protein 52 (FKBP52). FKBP52 was purified by using a prokaryotic expression plasmid containing the human cDNA. The purified protein could be phosphorylated at both tyrosine and serine or threonine residues, and only the phosphorylated forms of FKBP52 were shown to interact with the AAV single-stranded D-sequence probe. Furthermore, in in vitro DNA replication assays, tyrosine-phosphorylated FKBP52 inhibited AAV second-strand DNA synthesis by greater than 90%. Serine- or threonine-phosphorylated FKBP52 caused ≈40% inhibition, whereas dephosphorylated FKBP52 had no effect on AAV second-strand DNA synthesis. Deliberate overexpression of FKBP52 effectively reduced the extent of tyrosine phosphorylation of the protein, resulting in a significant increase in AAV-mediated transgene expression in human and murine cell lines. These studies corroborate the idea that the phosphorylation status of the cellular FKBP52 protein correlates strongly with AAV transduction efficiency, which may have important implications for the optimal use of AAV vectors in human gene therapy.

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  • The AAV ITR interacts with host proteins and can stimulate anti-viral and DNA damage response pathways.

    “it is known that the AAV ITR interacts with a number of host proteins and can stimulate anti-viral and DNA damage response pathways.12–16”

    From Adeno-Associated Virus Serotype-Specific Inverted Terminal Repeat Sequence Role in Vector Transgene Expression (2020) · cites this paper as [13]

    The Results show that phosphorylated cellular FKBP52 binds the AAV ITR D-sequence, supporting the host-protein interaction. The paper discusses effects on viral second-strand DNA synthesis and transgene expression, but does not show that the ITR stimulates antiviral or DNA damage response pathways. The indexed passages provide no page numbers. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Qing, K., Hansen, J., Weigel-Kelley, K. A., Tan, M., Zhou, S., & Srivastava, A.
Affiliations
  • Walther Cancer Foundation (US)
  • <!--label omitted: 4-->Avigen, Inc., Alameda, California 945014
  • Indiana University Hospital (US)
ORCID
Srivastava, Arun
Venue
Journal of Virology
Publisher
American Society for Microbiology
Published
2001-10
Volume
75
Issue
19
Pages
8968-8976
ISSN
  • 0022-538X (ISSN-L)
  • 1098-5514
DOI
10.1128/jvi.75.19.8968-8976.2001
PMC
PMC114465
OpenAlex
W2141482826
Cited by
126
References
7
Citations by year
2026: 1 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 6 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 5 · 2015: 4 · 2014: 3 · 2013: 3 · 2012: 3
FWCI
4.93
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Journal of Virology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL-58881, HL-53586, P01HL053586, R01HL058881)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK49218, P50DK049218, P30DK049218)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
Keywords
adeno-associated virus type 2, adeno-associated virus vectors, gene therapy vectors, FKBP52, FKBP, protein phosphorylation, epidermal growth factor receptor, transduction efficiency, transgene expression, HeLa cells, protein purification, immunosuppressants
MeSH terms
Dependovirus, Amino Acid Sequence, Animals, Genetic Vectors, HeLa Cells, Humans, Molecular Sequence Data, Transfection, Genetic Therapy, 3T3 Cells, Tacrolimus Binding Proteins, Mice

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