Roles of Integrins and Dopachrome Tautomerase (DCT) in HPV16 Infection of Human Keratinocytes
Cervical cancer is the fourth most common cancer in women worldwide. Persisting infection with a high-risk human papillomavirus (HPV) type is a major cause for cervical cancer. Regular Pap screening dramatically decreased the number of women with invasive cervical cancer in developed countries since 1950s, but cervical cancer is still a major killer in developing countries. Use of prophylactic HPV vaccines starting from the late 2000s is proven to be highly effective against infections with HPV16 and 18, the two most common HPV types that are detected in cervical cancer. However, because of the stigma about vaccinating teenagers against a sexually transmitted infection, the vaccination coverage is still lower compared to other vaccines (e.g. Tdap) even in developed countries. In less developed countries, the cost of the vaccines is also a limiting factor for the vaccination coverage. In this dissertation, I first focused on the roles of integrins in the initial steps of viral endocytosis into keratinocytes. Previous studies have shown that α6 integrin is necessary for infection. During my studies, I identified integrin α6β4 complex as necessary for infection in keratinocytes. β4 knockdown resulted in a significant decrease in HPV16 infection and also defective post-translational α6 processing and cell surface localization. I then investigated the importance of α6 processing in HPV16 infection. Furin is the α6-processing enzyme and by using a furin inhibitor, I showed that processing was not limiting cell membrane localization of α6, but the presence of β4 was. Because furin cleavage of viral L2 protein is necessary for infection, distinguishing furin activity in L2 and α6 processing is essential to understand the importance of α6 processing in HPV16 infection. In my second project, I investigated the roles of DCT in HPV16 infection. I showed that DCT depletion was almost detrimental for keratinocytes. DCT-depleted cells had higher oxidative stress levels, higher DNA damage, and slower proliferation. All of these cellular events prevented successful infection of the cells with HPV16 by causing the viral trafficking to halt at the endoplasmic reticulum.
Molecular biology|Cellular biology|Virology
Aksoy, Pinar, "Roles of Integrins and Dopachrome Tautomerase (DCT) in HPV16 Infection of Human Keratinocytes" (2017). ETD Collection for Fordham University. AAI10269089.