Fig. 5.

Cell cycle-dependent regulation of nuclear localisation for HPV E1 by cellular kinases. The prNLS of HPV E1 is shown (top), with the regulatory phosphorylation sites (blue), NLS (red) and NES (green), highlighted, as well as the binding partners that recognise them according to phosphorylation state (“P” indicates phosphorylation). The E1 NLS mediates IMPα/β1-mediated nuclear import inefficiently (black dotted arrow) (1a) but upon phosphorylation of S⁸⁹ and S⁹³ by ERK (and/or JNK for S⁸⁹), IMPα/β1 is able to bind the NLS more strongly to facilitate efficient nuclear import (1b). Once in the nucleus E1 is quickly exported back to the cytoplasm, through Crm1 (2a). Nuclear export is prevented by the nuclear kinases Cdk1/Cdk2 (2b), present during S and G₂ phases of cell cycle, which phosphorylate S¹⁰⁷ to prevent Crm1 binding to the NES, leading to strong nuclear accumulation/nuclear retention.