Cellular and Intraviral Interaction Partners of Papillomavirus E6 Protein

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URI: http://hdl.handle.net/10900/145908
Dokumentart: PhDThesis
Date: 2023-09-22
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biochemie
Advisor: Stehle, Thilo (Prof. Dr.)
Day of Oral Examination: 2023-01-31
DDC Classifikation: 570 - Life sciences; biology
Keywords: Papillomaviren
Other Keywords:
Protein-protein interaction
E6 protein
E7 protein
cottontail rabbit
Notch signaling
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Papillomaviruses are small DNA tumor viruses that infect humans and animals. Persistent infection with high-risk alpha-HPV can develop into cervical and anogenital cancer. HPV16, the most carcinogenic high-risk alpha type, causes >50% of HPV-associated cervical cancers. In addition, cutaneous beta HPV is highly associated with skin cancer in patients with epidermodysplasia verruciformis and individuals with immunosuppression. The carcinogenic E6 and E7 proteins are the major contributors to HPV-associated cancers. They are known to disrupt numerous cellular proteins and signaling pathways essential for tumor suppression. Cottontail rabbit papillomavirus (CRPV) induces papillomas in rabbit skin. It is an established animal model for HPV-mediated carcinogenesis, in which the viral E6 protein plays a critical role. Studies have shown that cutaneous beta-HPV, bovine PV, and mouse PV E6 proteins associate with mastermind-like 1 protein (MAML1) and subsequently inhibit Notch signaling, thereby impairing cell differentiation and proliferation. However, CRPV E6 differs from other E6 proteins in that it encodes an extended E6 protein (long E6, LE6) and an N-terminally truncated product (short E6, SE6). In this work, we describe the interaction between CRPV E6 proteins and MAML1 and their ability to down-regulate Notch signaling, which may be a way CRPV infection induces carcinogenesis similar to beta-HPV. The E6 protein interacts with cellular proteins to disrupt the cellular signaling pathway and can cooperate with E7 proteins to immortalize keratinocytes. The roles of E6 and E7 in the HPV life cycle and the development of carcinogenesis have previously been studied independently. However, a direct interaction between E6 and E7 has yet to be shown. In this thesis, a direct interaction between the E6 and E7 proteins of HPV16 and HPV31 is demonstrated in cell-based assays and verified using biophysical methods. In addition, the involvement of two E7 molecules and two E6 molecules in complex formation was demonstrated by analytical ultracentrifugation. Furthermore, the fluorescence polarization assay showed the binding affinity of the complexes is in a micromolar range. This interaction raises questions about the function of the complex in carcinogenesis and in the viral life cycle that requires further investigation.

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