The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection.
The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection.
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DOI：
10.1371/journal.pone.0043519
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kast WM
中科院分区：
文献类型：
--
作者：
Woodham AW;Da Silva DM;Skeate JG;Raff AB;Ambroso MR;Brand HE;Isas JM;Langen R;Kast WM
人乳头瘤病毒（HPV）是一种通过性传播的病毒，与宫颈癌的发生有因果关系。最常见的高危基因型HPV 16是一种必须进入宿主上皮细胞并将其双链DNA递送到细胞核的细胞内病毒。HPV衣壳蛋白在这些步骤中起着至关重要的作用。尽管这些衣壳蛋白-宿主细胞相互作用的关键性质，但HPV 16感染上皮细胞所需的精确细胞组分仍然未知。已经鉴定了HPV 16 L2次要衣壳蛋白的几个中和表位，其可以在病毒最初附着到细胞表面后抑制感染，这表明L2特异性二级受体或辅因子是感染所需的，但到目前为止还没有鉴定出特异性L2受体。在这里，我们证明了膜联蛋白A2异四聚体（A2 t）有助于HPV 16感染，并与HPV 16颗粒在上皮细胞表面上以L2依赖的方式共免疫沉淀。用内源性膜联蛋白A2配体、分泌性白细胞蛋白酶抑制剂（SLPI）或膜联蛋白A2抗体抑制A2 t可显著降低HPV 16感染。利用电子顺磁共振，我们证明了先前鉴定的L2（aa 108-120）的中和表位特异性地与A2 t的S100 A10亚基相互作用。此外，该L2区的突变显著降低了与A2 t的结合和HPV 16假病毒感染。此外，用shRNA下调A2 t显著降低了衣壳内化和HPV 16的感染。总之，这些发现表明，A2 t有助于HPV 16内化和上皮细胞的感染，并且这种相互作用依赖于L2次要衣壳蛋白的存在。
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.
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