Papillomaviruses are responsible for widespread infections in humans, causing pathegenesis ranging from inapparent infections to benign lesions, hyperplasia or cancers. Given the major public health concern due to HPV-associated cancers, most studies have focused on the early proteins expressed by the most clinically relevant HPVs most frequently found in cancers. Among the early proteins encoded by HPVs, the E2 protein regulates viral transcription, replication and mitotic segregation of the viral genome, mainly through the recruitment of host factors to the HPV regulatory region. E2 is therefore pivotal for both the viral productive cycle and for viral persistence, which is a major risk factor for cancer development. In addition, the E2 proteins have been shown to engage interactions important to directly modulate the host cell, thereby contributing to create suitable cell conditions for the successive stages of the HPV life cycle. Interestingly, some E2's roles have been demonstrated to be specific to the oncogenic HPVs, raising the idea that beyond its role in the general HPV regulation, E2 could also directly influence the fate of cancer development. This thesis aimed at providing an overview of E2's functions across multiple HPV genotypes and at identifying specific features that distinguish the different HPV pathological traits. We mapped the virus-host interaction networks of the E2 proteins from a panel of 12 HPVs selected to be representative of the HPV diversity. Clustering of E2's interaction profiles correlated with the HPV phylogeny, raising the notion that E2 could directly contribute to the HPV pathogenesis. This work also emphasizes that the E2 proteins, like many other viral proteins, tend to target highly connected cellular proteins (cellular hubs), which is presumed to be an evolutionary way to maximize viral impacts on the host. E2 predominantly targets a subset of key cellular processes, like transcriptional regulation, apoptosis, RNA metabolism, ubiquitination or intracellular transport, which both confirms already known E2's functions and points to potential new functions. In addition, this large-scale comparative approach offers a framework to pinpoint interactions that are specifically associated with the most represented HPVs in cancers and therefore can be used as targets for the development of new therapeutics. In particular, we identified a specific interaction between the E2 protein from HPV16 and a cellular protein, CCHCR1, involved in the regulation of keratinocyte proliferation. We determined that CCHCR1's interaction domain on E2 overlaps with that of BRD4, a major interactor of E2, inducing a physical competition between the two cellular proteins. This competitive binding affects BRD4-mediated enhancement of E2's transcriptional activity, suggesting that the interaction with CCHCR1 might have an impact on the role of E2 in the infected cell. In addition, we showed that CCHCR1 induces the docking of HPV16 E2 into the cytoplasm which could further affect E2's nuclear functions. We also demonstrated that CCHCR1 impairs HPV16 E2's induction of keratinocytes early differentiation, presumably resulting from the negative effect of CCHCR1 on the nuclear functions of E2. This effect could have drastic consequences on the oncogenic potential of HPV16 and could participate to high prevalence in cancers of HPV16. Taken together, these results enhance the general understanding of the impact of E2 during HPV infections and highlights its contribution in the HPV pathogenesis. E2 appears as a critical factor that participates in the global hijacking of the host cell to allow the virus to replicate despite the hostile environment. E2 also emerges as a viral component susceptible to directly influence the outcome of an HPV infection and to potentially impact on the preliminary steps of carcinogenic conversion.
