The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection.
Mucosotropic, high-risk human papillomaviruses (HPV) are sexually transmitted viruses that are causally associated with the development of cervical cancer. The most common high-risk genotype, HPV16, is an obligatory intracellular virus that must gain entry into host epithelial cells and deliver its...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3425544?pdf=render |
| _version_ | 1818399481987596288 |
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| author | Andrew W Woodham Diane M Da Silva Joseph G Skeate Adam B Raff Mark R Ambroso Heike E Brand J Mario Isas Ralf Langen W Martin Kast |
| author_facet | Andrew W Woodham Diane M Da Silva Joseph G Skeate Adam B Raff Mark R Ambroso Heike E Brand J Mario Isas Ralf Langen W Martin Kast |
| author_sort | Andrew W Woodham |
| collection | DOAJ |
| description | Mucosotropic, high-risk human papillomaviruses (HPV) are sexually transmitted viruses that are causally associated with the development of cervical cancer. The most common high-risk genotype, HPV16, is an obligatory intracellular virus that must gain entry into host epithelial cells and deliver its double stranded DNA to the nucleus. HPV capsid proteins play a vital role in these steps. Despite the critical nature of these capsid protein-host cell interactions, the precise cellular components necessary for HPV16 infection of epithelial cells remains unknown. Several neutralizing epitopes have been identified for the HPV16 L2 minor capsid protein that can inhibit infection after initial attachment of the virus to the cell surface, which suggests an L2-specific secondary receptor or cofactor is required for infection, but so far no specific L2-receptor has been identified. Here, we demonstrate that the annexin A2 heterotetramer (A2t) contributes to HPV16 infection and co-immunoprecipitates with HPV16 particles on the surface of epithelial cells in an L2-dependent manner. Inhibiting A2t with an endogenous annexin A2 ligand, secretory leukocyte protease inhibitor (SLPI), or with an annexin A2 antibody significantly reduces HPV16 infection. With electron paramagnetic resonance, we demonstrate that a previously identified neutralizing epitope of L2 (aa 108-120) specifically interacts with the S100A10 subunit of A2t. Additionally, mutation of this L2 region significantly reduces binding to A2t and HPV16 pseudovirus infection. Furthermore, downregulation of A2t with shRNA significantly decreases capsid internalization and infection by HPV16. Taken together, these findings indicate that A2t contributes to HPV16 internalization and infection of epithelial cells and this interaction is dependent on the presence of the L2 minor capsid protein. |
| first_indexed | 2024-12-14T07:21:22Z |
| format | Article |
| id | doaj.art-a95a282ebc4a4c70b78031dcbef4845a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T07:21:22Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-a95a282ebc4a4c70b78031dcbef4845a2022-12-21T23:11:37ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0178e4351910.1371/journal.pone.0043519The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection.Andrew W WoodhamDiane M Da SilvaJoseph G SkeateAdam B RaffMark R AmbrosoHeike E BrandJ Mario IsasRalf LangenW Martin KastMucosotropic, high-risk human papillomaviruses (HPV) are sexually transmitted viruses that are causally associated with the development of cervical cancer. The most common high-risk genotype, HPV16, is an obligatory intracellular virus that must gain entry into host epithelial cells and deliver its double stranded DNA to the nucleus. HPV capsid proteins play a vital role in these steps. Despite the critical nature of these capsid protein-host cell interactions, the precise cellular components necessary for HPV16 infection of epithelial cells remains unknown. Several neutralizing epitopes have been identified for the HPV16 L2 minor capsid protein that can inhibit infection after initial attachment of the virus to the cell surface, which suggests an L2-specific secondary receptor or cofactor is required for infection, but so far no specific L2-receptor has been identified. Here, we demonstrate that the annexin A2 heterotetramer (A2t) contributes to HPV16 infection and co-immunoprecipitates with HPV16 particles on the surface of epithelial cells in an L2-dependent manner. Inhibiting A2t with an endogenous annexin A2 ligand, secretory leukocyte protease inhibitor (SLPI), or with an annexin A2 antibody significantly reduces HPV16 infection. With electron paramagnetic resonance, we demonstrate that a previously identified neutralizing epitope of L2 (aa 108-120) specifically interacts with the S100A10 subunit of A2t. Additionally, mutation of this L2 region significantly reduces binding to A2t and HPV16 pseudovirus infection. Furthermore, downregulation of A2t with shRNA significantly decreases capsid internalization and infection by HPV16. Taken together, these findings indicate that A2t contributes to HPV16 internalization and infection of epithelial cells and this interaction is dependent on the presence of the L2 minor capsid protein.http://europepmc.org/articles/PMC3425544?pdf=render |
| spellingShingle | Andrew W Woodham Diane M Da Silva Joseph G Skeate Adam B Raff Mark R Ambroso Heike E Brand J Mario Isas Ralf Langen W Martin Kast The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection. PLoS ONE |
| title | The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection. |
| title_full | The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection. |
| title_fullStr | The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection. |
| title_full_unstemmed | The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection. |
| title_short | The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection. |
| title_sort | s100a10 subunit of the annexin a2 heterotetramer facilitates l2 mediated human papillomavirus infection |
| url | http://europepmc.org/articles/PMC3425544?pdf=render |
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