HPV type 16 E6 and NFX1-123 Augment JNK Signaling to Mediate Keratinocyte Differentiation and L1 Expression

Abstract The HPV life cycle is differentiation-dependent, with cellular differentiation driving initiation of the late, productive stage of the viral life cycle. Here, we identify a role for the protein NFX1–123 in regulating keratinocyte differentiation and events of the late HPV life cycle. NFX1–123 itself increased with differentiation of epithelial cells. Greater NFX1–123 augmented differentiation marker expression and JNK phosphorylation in differentiating 16E6-expressing human foreskin keratinocytes (16E6 HFKs). This was associated with altered expression of MKK4 and MKK7, upstream kinase regulators of JNK phosphorylation. Modulating levels of NFX1–123 in HPV16-positive W12E cells recapitulated the effects on differentiation markers, JNK phosphorylation, and MKK4/7 seen in 16E6 HFKs. Crucially, levels of NFX1–123 also correlated with expression of L1, the capsid protein of HPV. Altogether, these studies define a role for NFX1–123 in mediating epithelial differentiation through the JNK signaling pathway, potentially linking expression of cellular genes and HPV genes during differentiation.