Identification and Characterization of Pyk2 Function During HPV16 Infection

Elinor Yasmin Gottschalk, Fordham University

Abstract

Persistent infection with high-risk types of human papillomaviruses (HPVs) is a known cause of cancer. HPV-related cancers are a globally significant health burden and are potentially avoidable through the prevention of HPV infection. Four types of HPVs (mainly HPV16) are primarily responsible for 99% of cervical cancers, 95% of anal cancers, 60% to 70% of genital cancers, and approximately 70% of oropharyngeal cancers. The current vaccines (Gardasil, Cervarix, and Gardasil9) are very effective at preventing HPV infection. However, there are concerns about vaccine coverage in developed countries and the accessibility to the vaccines in less developed regions of the world, which are disproportionately affected by HPV-related cancers. There has been substantial work on the infectious pathway of HPV16, although specifics of viral binding, endocytosis, and trafficking remain unclear. A detailed understanding of HPV infection is vital to the development of additional, broad-acting, and accessible preventative therapies. The infectious process of a virus can be complex and typically involve many cellular components. Understanding this process can not only help us understand viral infection in the context of disease, but also to discover novel cellular functions for proteins.^ There are two critical stages during HPV infection: viral entry at the plasma membrane of target cells and trafficking of the viral DNA from the plasma membrane to the nucleus. My dissertation focuses on the cellular protein tyrosine kinase 2 (Pyk2) and its involvement in HPV16 infection of human basal keratinocytes (HaCaT cells). I show that Pyk2 depletion and Pyk2 inhibition result in a significant decrease in HPV16 infection, but did not prevent viral entry at the plasma membrane. The depletion and inhibition of Pyk2 resulted in altered endosomal-lysosomal trafficking of HPV16 and accelerated unfolding of the viral capsid. Furthermore, I demonstrate that Pyk2 and the minor viral capsid protein, L2, have the ability to interact. My data suggest that the Pyk2-L2 interaction requires the Pyk2 FERM domain, but does not require Pyk2 kinase activity. Additionally, I observe cell cycle arrest in Pyk2-depleted cells but not in Pyk2-inhibited cells, suggesting that Pyk2 has a role in cell cycle that is independent of its function as a protein kinase. Taken together my results suggest novel roles for Pyk2 in HPV16 trafficking during the infectious process and in cell cycle and endolysosomal trafficking in human keratinocytes.^

Subject Area

Biology|Virology

Recommended Citation

Gottschalk, Elinor Yasmin, "Identification and Characterization of Pyk2 Function During HPV16 Infection" (2018). ETD Collection for Fordham University. AAI10812602.
https://fordham.bepress.com/dissertations/AAI10812602

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