Infection with the oncogenic human papillomavirus type 59 alters protein components of the cornified cell envelope

Abstract

Infection of the genital tract with human papillomaviruses (HPVs) leads to proliferative and dysplastic epithelial lesions. The mechanisms used by the virus to escape the infected keratinocyte are not well understood. Infection of keratinocytes with HPV does not cause lysis, the mechanism used by many viruses to release newly formed virions. For HPV 11, a type associated with a low risk of neoplastic disease, the cornified cell envelope (CCE) of infected keratinocytes is thin and fragile, and transcription of loricrin, the major CCE protein, is reduced. The effects of high-risk HPV infection on components of the CCE have not been previously reported. HPV 59, an oncogenic genital type related to HPV types 18 and 45 was identified in a condylomata acuminata lesion. An extract of this lesion was used to infect human foreskin fragments, which were grown in athymic mice as xenografts. Continued propagation using extracts of xenografts permitted growth of additional HPV 59-infected xenografts. CCEs purified from HPV 59-infected xenografts displayed subtle morphologic abnormalities compared to those derived from uninfected xenografts. HPV 59-infected xenografts revealed dysplastic-appearing cells with mitotic figures. Detection of loricrin, involucrin, and cytokeratin 10 was reduced in HPV 59-infected epithelium, while small proline-rich protein 3 (SPR3) was increased. Reduction in loricrin was most apparent in regions of epithelium containing abundant HPV 59 DNA. Compared to uninfected epithelium, loricrin transcription was decreased in HPV 59-infected epithelium. We conclude that HPV 59 shares with HPV 11 the ability to alter CCE components and to specifically reduce transcription of the loricrin gene. Because loricrin is the major CCE protein, a reduction in this component could alter the physical properties of the CCE, thus facilitating virion release.

Cutaneous Human Papillomaviruses Down-regulate AKT1, whereas AKT2 Up-regulation and Activation Associates with Tumors

“…Anogenital HPV infection produces late terminal differentiation changes and changes to the cornified envelope of mucosal epithelium (20, 21). We show that cutaneous HPV8 early genes down-regulate filaggrin, a key late terminal differentiation marker that is processed through multiple steps to produce a small molecular weight form crucial for terminal differentiation [Fig.…”

“…We speculate that AKT1 activity is targeted by cutaneous HPVs to render the cornified envelope “fragile” to effect escape. Anogenital HPV-associated change to cornified envelopes is well documented and also achieved through changes to late terminal differentiation proteins (20, 21) and, possibly, by expression of the HPV E1∧E4 early gene, which binds keratin and causes keratin collapse (27). However, cutaneous papillomaviruses express an E1∧E4 protein that is unable to induce intermediate filament collapse (28).…”

“…Therefore, to accomplish the release of virus particles from the terminally differentiated keratinocytes of stratum corneum, HPV has to escape from the keratinocyte cornified envelope, a protein-lipid–linked cell envelope designed to provide a biological barrier (19). Infection of mucosal keratinocytes by anogenital HPVs induces cornified envelope fragility by a variety of means (20, 21). The mechanism used by cutaneous HPV viruses for disruption of the tough epidermal cornified envelope is unknown, and because epidermal AKT activity is linked to stratum corneum formation (18), we speculated that HPV may achieve squame disruption by modulating AKT activity.…”

Calprotectin and the Initiation and Progression of Head and Neck Cancer

“…S100A8 and S100A9 , however, do not appear to be the only members of EDC regulated by HPV. Involucrin ( IVL ) and loricrin ( LOR ) are transcriptionally downregulated by E6 and E7 HPV oncoproteins in proliferating and differentiating human foreskin keratinocytes (Lehr and Brown 2003; Gyöngyösi et al 2012). Specifically, involucrin is indirectly suppressed by E6 oncoprotein through HPV-mediated downregulation of transcription factor C/EBPα (Marthaler et al 2017).…”

Effects of human papillomavirus (HPV) type 16 oncoproteins on the expression of involucrin in human keratinocytes

“…Indeed, HPV 16 E6 was shown to modulate the expression of several differentiation-associated genes in human foreskin keratinocytes [13]. Using a xenograft model, Lehr and co-workers showed that infection of human keratinocytes by certain HPVs (type 11 and 59) causes altered expression of certain CCE (cornified cell envelope) proteins, such as loricrin and small proline rich proteins (SPRR), both on the mRNA and on the protein level [14,15]. However, it is not known whether the HPV oncoproteins have effects on the promoters of differentiation-regulated genes or exert their effects post-transcriptionally.…”