Manipulation of Epithelial Differentiation by HPV Oncoproteins

Abstract

Papillomaviruses replicate and cause disease in stratified squamous epithelia. Epithelial differentiation is essential for the progression of papillomavirus replication, but differentiation is also impaired by papillomavirus-encoded proteins. The papillomavirus E6 and E7 oncoproteins partially inhibit and/or delay epithelial differentiation and some of the mechanisms by which they do so are beginning to be defined. This review will outline the key features of the relationship between HPV infection and differentiation and will summarize the data indicating that papillomaviruses alter epithelial differentiation. It will describe what is known so far and will highlight open questions about the differentiation-inhibitory mechanisms employed by the papillomaviruses.

Keywords: HPV; differentiation; epithelial; transformation; virus.

Figure 1

Human papillomavirus (HPV) replication requires and impairs epithelial differentiation. A schematic of epithelial differentiation in the absence (A) and presence (B) of HPV infection. In uninfected cells, self-renewing basal keratinocytes attach to the basement membrane. When keratin 5 and keratin 14-positive basal cells divide, one daughter cell can progress into the spinous layers and express keratins 1 and 10. Terminal differentiation and progression into the granular and cornified layers is marked by the expression of fillagrin and involucrin. Suprabasal epithelial cells are generally not proliferative. In an HPV-infected epithelium, proliferation is uncoupled from differentiation. Markers of proliferation are expressed and differentiation-related gene expression is impaired in suprabasal cells.

Figure 2

Genus beta HPV E6 bind MAML1 to inhibit NOTCH signaling. A schematic of activated NOTCH signaling in the absence (A) and presence (B) of genus beta HPV E6. Upon activation of the NOTCH signaling pathway, proteolytic cleavage of NOTCH releases the NOTCH intracellular domain (ICD), which can translocate to the nucleus. It displaces transcriptional repressors and forms a transcriptionally active complex including NOTCH, MAML1, and RBP-J. Genus beta HPV E6 bind to an LxxLL motif present in the MAML1 C-terminus. The oncoprotein does not disrupt formation of the transcription complex but does inhibit NOTCH signaling.