Annexin A2 and S100A10 Regulate Human Papillomavirus Type 16 Entry and Intracellular Trafficking in Human Keratinocytes

Abstract

Human papillomaviruses (HPVs) cause benign and malignant tumors of the mucosal and cutaneous epithelium. The initial events regulating HPV infection impact the establishment of viral persistence, which is requisite for malignant progression of HPV-infected lesions. However, the precise mechanisms involved in HPV entry into host cells, including the cellular factors regulating virus uptake, are not clearly defined. We show that HPV16 exposure to human keratinocytes initiates epidermal growth factor receptor (EGFR)-dependent Src protein kinase activation that results in phosphorylation and extracellular translocation of annexin A2 (AnxA2). HPV16 particles interact with AnxA2 in association with S100A10 as a heterotetramer at the cell surface in a Ca 2؉ -dependent manner, and the interaction appears to involve heparan-sulfonated proteoglycans. We show multiple lines of evidence that this interaction promotes virus uptake into host cells. An antibody to AnxA2 prevents HPV16 internalization, whereas an antibody to S100A10 blocks infection at a late endosomal/lysosomal site. These results suggest that AnxA2 and S100A10 have separate roles during HPV16 binding, entry, and trafficking. Our data additionally imply that AnxA2 and S100A10 may be involved in regulating the intracellular trafficking of virus particles prior to nuclear delivery of the viral genome.

Mycoplasma Hyorhinis Infection Promotes NF-κB–Dependent Migration of Gastric Cancer Cells

“…EGFR plays a role in regulating ANXA2 phosphorylation and localization (30,31). By coimmunoprecipitation assay, we found that p37 interacted with both ANXA2 and EGFR (Fig.…”

Emerging functions as host cell factors – an encyclopedia of annexin-pathogen interactions

“…The heterotetrameric complex formed by AnxA2 and its interaction partner S100A10 (formerly known as p11, belongs to the S100 protein family of Ca 2+ binding proteins) was proposed to contribute to the internalization of the most common high-risk human papillomavirus genotype, HPV16, which causes benign and malignant tumors of the mucosal and cutaneous epithelium. HPV16 elicits AnxA2 translocation to the cell surface (Dziduszko and Ozbun, 2013), and the cell surface AnxA2/S100A10 complex is essential for entry of the virus into the host cell, acting presumably as receptor for the HPV minor capsid protein L2 (Woodham et al, 2012;Dziduszko and Ozbun, 2013). Interestingly, small molecule inhibitors of the AnxA2/S100A10 complex substantially reduced HPV16 infection in a cell culture model (Woodham et al, 2015).…”

“…Latent membrane protein 1 (LMBP1) encoded by Epstein-Barr virus was shown to activate protein kinase C, resulting in AnxA2 phosphorylation and nuclear translocation, with the nuclear pool of AnxA2 supporting DNA synthesis and cell proliferation (Luo et al, 2008). HPV16 was reported to cause epidermal growth factor receptor (EGFR)-dependent activation of src kinase, resulting in phosphorylation and extracellular translocation of AnxA2 to function in HPV16 internalization (Dziduszko and Ozbun, 2013). Virulent strains of Mycobacterium tuberculosis induce proteolytic cleavage of AnxA1 on the surface of infected cells, thereby interfering with formation of the apoptotic envelope (Gan et al, 2008).…”

Annexins in Translational Research: HIDDEN Treasures to Be Found

“…The complex most likely interacts with the HPV minor capsid protein L2 [135,136]. Importantly, interfering with AnxA2/S100A10 complex through the use of small molecule inhibitors markedly impairs HPV16 infection in a cell culture model [137].…”