br Acknowledgements The study of

Acknowledgements The study of RING-type E3s continues to grow extremely rapidly. We regret that it was possible to only cite a fraction of the outstanding primary publications in this field. This work was supported by the National Institute of General Medical Sciences grants R01 GM088055 and R01 GM098503 (R.E.K.) and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (A.M.W.).
Introduction Papillomaviruses infect stratifying epithelia that are programmed to undergo terminal differentiation. Upon entry into basal cells, a single closed circular double stranded viral episome replicates to perhaps 10–50 copies per cell. This stage depends on host replicative factors; cellular and viral proteins are not packaged within the virion. Despite this initial amplification, PVs only express trace amounts of viral proteins and do not cause lytic infections. The E1 and E2 proteins are required for PV replication and mutations that render these inactive eventuate in either integration into stochastic chromosomal locations or loss of viral DNA [(Schiller et al., 1989), reviewed in (Kadaja et al., 2009)]. The E2 protein binds directly to and recruits the E1 DNA helicase to their recognition motifs that form the viral origin of replication (Androphy et al., 1987, Mohr et al., 1990). E1 monomers assemble into active double hexamers, which requires release from the E2 protein (Sanders and Stenlund, 1998). Several post-translational modifications of E2 protein are known to regulate its activities. We recently reported the acetylation of the bovine papillomavirus (BPV-1) E2 protein at lysine (K) 111 and K112 (Quinlan et al., 2013) and HPV-31 E2 at K111, and that this was necessary for unwinding of the replication fork (Thomas and Androphy, 2018). Phosphorylation of E2 on specific serine and threonine residues are known to affect its stability, NVP-CGM097 receptor binding and protein-protein interactions [(Chang et al., 2014), reviewed in (McBride, 2013)]. Recently, we detected tyrosine (Y) phosphorylation of BPV-1 E2 at amino acid 102 and that the phosphomimetic glutamate substitution reduced E2 transcription and replication activity (Culleton et al., 2017). Subsequently, fibroblast growth factor receptor-3 (FGFR3) was found to induce phosphorylation of tyrosine that restricts PV genome replication, although this was not mediated through Y102 (Xie et al., 2017). Fibroblast growth factor receptors (FGFRs) are a group of four transmembrane tyrosine kinase receptors with multiple isoforms (Gong, 2014). The FGF signaling pathway regulates multiple biological processes such as angiogenesis, and tissue development and regeneration (Touat et al., 2015). FGFRs are involved in varying stages of viral infections. For example, FGFR1 may be a co-receptor for adeno-associated virus (AAV) 2 (Qing et al., 1999) and AAV-3 (Blackburn et al., 2006). FGFR1 suppresses influenza virus replication (Liu et al., 2015) and is activated by Epstein Barr Virus protein latent membrane protein 1 (LMP1) facilitating epithelial cell transformation (Lo et al., 2015). FGFR4 is involved in infectivity of a modified Influenza virus (Konig et al., 2010). FGFR1 and FGFR4 expression were increased in long-term Kaposi's sarcoma-associated herpesvirus (KSHV) infected telomerase-immortalized human umbilical vein endothelial cells (An et al., 2006). HPV-16 E5 protein targeting of FGFR2 inhibits autophagy, possibly affecting the early stages of HPV infection (Belleudi et al., 2015). In a search for tyrosine kinases in complex with the E2 protein, an activated FGFR3 mutant was shown to suppress transient viral DNA replication (Xie et al., 2017). However, this did not require phosphorylation of E2 at Y102, inferring that another tyrosine kinase might target this residue and that other phosphotyrosines could be mediating the inhibitory effect of FGFR3. Our next goal was to determine if another FGFR family member complexes with and regulates E2 function. We found that only FGFR2 interacted with BPV-1 E2 while FGFR-1, −2, and −4 complex with HPV-16 and HPV-31 E2. However only endogenous FGFR-2 could be co-immunoprecipitated (co-ip’d) with HPV-16 E2.