The VP1 capsid protein of adeno-associated virus type 2 is carrying a phospholipase A2 domain required for virus infectivity
Abstract
The unique region of the VP1 protein of parvoviruses was proposed to contain a parvoviral phospholipase A2 (pvPLA2) motif. Here, PLA2 activity is shown in the unique region of adeno-associated virus type 2 (AAV-2) VP1 when expressed as an isolated domain in bacteria. Mutations in this region of the capsid protein strongly reduced the infectivity of mutant virions in comparison to wild-type AAV-2. This correlated with effects on the activity of PLA2. The mutations had no influence on capsid assembly, packaging of viral genomes into particles or binding to and entry into HeLa cells. However, a delayed onset and reduced amount of early gene expression, as measured by Rep immunofluorescence, was observed. These results suggest that pvPLA2 activity is required for a step following perinuclear accumulation of virions but prior to early gene expression.
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A phospholipase domain essential for viral infectivity has been identified in the unique N terminus of Vp1.
“A phospholipase domain, essential for viral infectivity, has been identified in the unique N terminus of Vp1 (19, 53).”
From Packaging Capacity of Adeno-Associated Virus Serotypes: Impact of Larger Genomes on Infectivity and Postentry Steps (2005) · cites this paper as [19]
VP1 contains a phospholipase A2 site in its unique N-terminus (VP1u) that is important for endo/lysosomal escape during cellular trafficking and viral infectivity.
“VP1 is encoded within the entire cap ORF, it is approximately 735 aa in length, 87 kDa in molecular weight (MW) and contains a phospholipase A2 (PLA2) site that is important for endo/lysosomal escape during cellular trafficking and viral infectivity in its unique N-terminus (VP1u) [7].”
From Understanding Capsid Assembly and Genome Packaging for Adeno-Associated Viruses (2017) · cites this paper as [7]
Cites
Grimm, D., Kern, A., Pawlita, M., Ferrari, F. K., Samulski, R. J., & Kleinschmidt, J. A. (1999) · Gene Therapy · doi:10.1038/sj.gt.3300946 · Cited by 195 · see citing works
Self-citationWistuba, A., Weger, S., Kern, A., & Kleinschmidt, J. A. (1995) · Journal of Virology · doi:10.1128/jvi.69.9.5311-5319.1995 · Cited by 147 · cited 1× · see citing works
“The next detectable event during a productive AAV-2 infection is early gene expression (Trempe et al., 1987 ; Redemann et al., 1989 ; Wistuba et al., 1995).”
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Gene therapy using adeno-associated virus vectors
Daya, S., & Berns, K. I. (2008) · Clinical Microbiology Reviews · doi:10.1128/cmr.00008-08 · Cited by 926 · see citing works
Grieger, J. C., & Samulski, R. J. (2005) · Journal of Virology · doi:10.1128/jvi.79.15.9933-9944.2005 · Cited by 419 · see citing works
Identification of a heparin-binding motif on adeno-associated virus type 2 capsids
Kern, A., Schmidt, K., Leder, C., Müller, O. J., Wobus, C. E., Bettinger, K., Von der Lieth, C. W., King, J. A., & Kleinschmidt, J. A. (2003) · Journal of Virology · doi:10.1128/jvi.77.20.11072-11081.2003 · Cited by 380 · see citing works
Self-citationIn Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector
Zinn, E., Pacouret, S., Khaychuk, V., Turunen, H. T., Carvalho, L. S., Andres-Mateos, E., Shah, S., Shelke, R., Maurer, A. C., Plovie, E., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.07.019 · Cited by 310 · see citing works
Capsid modifications for targeting and improving the efficacy of AAV vectors
Büning, H., & Srivastava, A. (2019) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2019.01.008 · Cited by 260 · see citing works
Intracellular transport of recombinant adeno-associated virus vectors
Nonnenmacher, M., & Weber, T. (2012) · Gene Therapy · doi:10.1038/gt.2012.6 · Cited by 258 · see citing works
Intracellular trafficking of adeno-associated viral vectors
Ding, W., Zhang, L., Yan, Z., & Engelhardt, J. F. (2005) · Gene Therapy · doi:10.1038/sj.gt.3302527 · Cited by 251 · see citing works
Basic Biology of Adeno-Associated Virus (AAV) Vectors Used in Gene Therapy
Balakrishnan, B., & Jayandharan, G. (2014) · Current Gene Therapy · doi:10.2174/1566523214666140302193709 · Cited by 225 · see citing works
AAV Capsid Structure and Cell Interactions
Agbandje-McKenna, M., & Kleinschmidt, J. (2012) · Methods in Molecular Biology · doi:10.1007/978-1-61779-370-7_3 · Cited by 215 · see citing works
Self-citationWarrington, K. H., Gorbatyuk, O. S., Harrison, J. K., Opie, S. R., Zolotukhin, S., & Muzyczka, N. (2004) · Journal of Virology · doi:10.1128/jvi.78.12.6595-6609.2004 · Cited by 205 · see citing works
Bleker, S., Sonntag, F., & Kleinschmidt, J. A. (2005) · Journal of Virology · doi:10.1128/jvi.79.4.2528-2540.2005 · Cited by 200 · see citing works
Self-citationKronenberg, S., Böttcher, B., von der Lieth, C. W., Bleker, S., & Kleinschmidt, J. A. (2005) · Journal of Virology · doi:10.1128/jvi.79.9.5296-5303.2005 · Cited by 198 · see citing works
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Molecular evolution of adeno-associated virus for enhanced glial gene delivery
Koerber, J. T., Klimczak, R., Jang, J.-H., Dalkara, D., Flannery, J. G., & Schaffer, D. V. (2009) · Molecular Therapy · doi:10.1038/mt.2009.184 · Cited by 181 · see citing works
DNA Shuffling of Adeno-associated Virus Yields Functionally Diverse Viral Progeny
Koerber, J. T., Jang, J.-H., & Schaffer, D. V. (2008) · Molecular Therapy · doi:10.1038/mt.2008.167 · Cited by 181 · see citing works
Grieger, J. C., Snowdy, S., & Samulski, R. J. (2006) · Journal of Virology · doi:10.1128/jvi.02723-05 · Cited by 172 · see citing works
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Nam, H.-J., Gurda, B. L., McKenna, R., Potter, M., Byrne, B., Salganik, M., Muzyczka, N., & Agbandje-McKenna, M. (2011) · Journal of Virology · doi:10.1128/jvi.05305-11 · Cited by 108 · see citing works
Heparin binding induces conformational changes in Adeno-associated virus serotype 2
Levy, H. C., Bowman, V. D., Govindasamy, L., McKenna, R., Nash, K., Warrington, K., Chen, W., Muzyczka, N., Yan, X., Baker, T. S., et al. (2009) · Journal of Structural Biology · doi:10.1016/j.jsb.2008.12.002 · Cited by 110 · see citing works
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Rossi, A., Dupaty, L., Aillot, L., Zhang, L., Gallien, C., Hallek, M., Odenthal, M., Adriouch, S., Salvetti, A., & Büning, H. (2019) · Scientific Reports · doi:10.1038/s41598-019-40071-1 · Cited by 85 · see citing works
Self-citationStieger, K., Schroeder, J., Provost, N., Mendes-Madeira, A., Belbellaa, B., Meur, G. L., Weber, M., Deschamps, J.-Y., Lorenz, B., Moullier, P., et al. (2009) · Molecular Therapy · doi:10.1038/mt.2008.283 · Cited by 88 · see citing works
Dobrowsky, T., Gianni, D., Pieracci, J., & Suh, J. (2021) · Current Opinion in Biomedical Engineering · doi:10.1016/j.cobme.2021.100353 · Cited by 90 · see citing works
Understanding Capsid Assembly and Genome Packaging for Adeno-Associated Viruses
Bennett, A., Mietzsch, M., & Agbandje-McKenna, M. (2017) · Future Virology · doi:10.2217/fvl-2017-0011 · Cited by 82 · see citing works
Hsu, H.-L., Brown, A., Loveland, A. B., Lotun, A., Xu, M., Luo, L., Xu, G., Li, J., Ren, L., Su, Q., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17047-1 · Cited by 63 · see citing works
AAV capsid design: A Goldilocks challenge
Zolotukhin, S., & Vandenberghe, L. H. (2022) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2022.01.003 · Cited by 64 · see citing works
Manufacturing Clinical Grade Recombinant Adeno-Associated Virus Using Invertebrate Cell Lines
Kotin, R. M., & Snyder, R. O. (2017) · Human Gene Therapy · doi:10.1089/hum.2017.042 · Cited by 59 · see citing works
Adeno-associated virus capsid antigen presentation is dependent on endosomal escape
Li, C., He, Y., Nicolson, S., Hirsch, M., Weinberg, M. S., Zhang, P., Kafri, T., & Samulski, R. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66611 · Cited by 61 · see citing works
François, A., Bouzelha, M., Lecomte, E., Broucque, F., Penaud-Budloo, M., Adjali, O., Moullier, P., Blouin, V., & Ayuso, E. (2018) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2018.07.004 · Cited by 50 · see citing works
Jose, A., Mietzsch, M., Smith, J. K., Kurian, J., Chipman, P., McKenna, R., Chiorini, J., & Agbandje-McKenna, M. (2019) · Journal of Virology · doi:10.1128/jvi.01394-18 · Cited by 44 · see citing works
Li, C., Hirsch, M., DiPrimio, N., Asokan, A., Goudy, K., Tisch, R., & Samulski, R. J. (2009) · Journal of Virology · doi:10.1128/jvi.00278-09 · Cited by 42 · see citing works
Engineered Capsids for Efficient Gene Delivery to the Retina and Cornea
Frederick, A., Sullivan, J., Liu, L., Adamowicz, M., Lukason, M., Raymer, J., Luo, Z., Jin, X., Rao, K. N., & O'Riordan, C. (2020) · Human Gene Therapy · doi:10.1089/hum.2020.070 · Cited by 35 · see citing works
Efficient capsid antigen presentation from adeno-associated virus empty virions in vivo
Pei, X., Earley, L. F., He, Y., Chen, X., Hall, N. E., Samulski, R. J., & Li, C. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00844 · Cited by 35 · see citing works
“Although both full and empty virions contain VP1, which harbors both the phospholipase A2 (PLA2) domain and nuclear localization signals (NLSs) required for efficient intracellular trafficking (11, 20, 21), empty particles are deficient in exposure of the N-terminal of VP1/2 of AAV virions when compared to full partic…”
BackgroundTang, Y., Yan, Z., Lin, S., Huntemann, E. D., Feng, Z., Park, S.-Y., Sun, X., Yuen, E., & Engelhardt, J. F. (2020) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2020.09.008 · Cited by 21 · see citing works
- Authors
- Girod, A., Wobus, C. E., Zádori, Z., Ried, M., Leike, K., Tijssen, P., Kleinschmidt, J. A., & Hallek, M.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- German Cancer Research Center (DE)
- Institut National de la Recherche Scientifique (CA)
- Helmholtz Munich (DE)
- Corresponding author
- Hallek, Michael
- Venue
- Journal of General Virology
- Publisher
- Microbiology Society
- Published
- 2002-05-01
- Volume
- 83
- Issue
- 5
- Pages
- 973-978
- ISSN
- 0022-1317 (ISSN-L)
- 1465-2099
- OpenAlex
- W2141797403
- Cited by
- 354
- References
- 2
- Citations by year
- 2026: 16 · 2025: 17 · 2024: 18 · 2023: 18 · 2022: 16 · 2021: 22 · 2020: 23 · 2019: 22 · 2018: 15 · 2017: 11 · 2016: 9 · 2015: 18 · 2014: 11 · 2013: 12 · 2012: 18
- FWCI
- 7.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of General Virology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Infectious Diseases › Parvovirus B19 Infection Studies
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Keywords
- adeno-associated virus type 2, VP1 capsid protein, viral infectivity, early gene expression, Rep protein, capsid assembly, viral entry, perinuclear accumulation
- MeSH terms
- Dependovirus, Capsid, HeLa Cells, Humans, Phospholipases A, Genetic Therapy, Virus Assembly, Capsid Proteins, Phospholipases A2
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