Functions of Papillomavirus E8^E2 Proteins in Tissue Culture and In Vivo

Kuehner, Franziska; Stubenrauch, Frank

doi:10.3390/v14050953

Cited by 7 publications

(6 citation statements)

References 81 publications

(166 reference statements)

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“…26 E8^E2 restricts viral genome amplification to this low-level by repressing E1/E2-mediated viral genome replication and transcription. 27 Basal layer daughter cells each contain an equal number of HPV genomes, which are thought to be relatively silent transcriptionally. 25 When these cells begin to differentiate into the spinous layer, they initiate full viral gene expression.…”

Section: The Hpv Life Cycle and The Infected Epitheliummentioning

confidence: 99%

“…Initial gene expression in an infected basal epithelial cell involves the expression of viral early proteins E1 and E2, 25 which activate viral replication leading to amplification of the incoming genome to between 50 and 100 viral genomes 26 . E8^E2 restricts viral genome amplification to this low‐level by repressing E1/E2‐mediated viral genome replication and transcription 27 . Basal layer daughter cells each contain an equal number of HPV genomes, which are thought to be relatively silent transcriptionally 25 .…”

Section: Introductionmentioning

confidence: 99%

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The human papillomavirus late life cycle and links to keratinocyte differentiation

Kirk,

Graham

2024

Journal of Medical Virology

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Regulation of human papillomavirus (HPV) gene expression is tightly linked to differentiation of the keratinocytes the virus infects. HPV late gene expression is confined to the cells in the upper layers of the epithelium where the virus capsid proteins are synthesized. As these proteins are highly immunogenic, and the upper epithelium is an immune‐privileged site, this spatial restriction aids immune evasion. Many decades of work have contributed to the current understanding of how this restriction occurs at a molecular level. This review will examine what is known about late gene expression in HPV‐infected lesions and will dissect the intricacies of late gene regulation. Future directions for novel antiviral approaches will be highlighted.

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Section: The Hpv Life Cycle and The Infected Epitheliummentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The human papillomavirus late life cycle and links to keratinocyte differentiation

Kirk,

Graham

2024

Journal of Medical Virology

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“…Both domains are linked by a non-conserved, unstructured “hinge” region of approximately 80 aa ( 6 ). In addition to full-length E2, PV express a spliced transcript encoding an E8^E2 fusion protein ( 7 ). The E8^E2 transcript is processed at a splice donor in the E1 gene and the major splice acceptor in the E2/E4 region ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to full-length E2, PV express a spliced transcript encoding an E8^E2 fusion protein ( 7 ). The E8^E2 transcript is processed at a splice donor in the E1 gene and the major splice acceptor in the E2/E4 region ( 7 ). The E8^E2 protein consists of the short E8 domain (~10 aa) which is linked to the E2 hinge-DNA binding/dimerization domain ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

“…The E8^E2 transcript is processed at a splice donor in the E1 gene and the major splice acceptor in the E2/E4 region ( 7 ). The E8^E2 protein consists of the short E8 domain (~10 aa) which is linked to the E2 hinge-DNA binding/dimerization domain ( 7 ). E8^E2 interacts with E2-binding sites (E2BS) and acts as a repressor of viral transcription and genome replication ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

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Mus musculus papillomavirus 1 E8^E2 represses expression of late protein E4 in basal-like keratinocytes via NCoR/SMRT-HDAC3 co-repressor complexes to enable wart formation in vivo

Kuehner

Wong

Straub

et al. 2023

mBio

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High-risk human papillomaviruses (PV) account for approximately 600,000 new cancers per year. The early protein E8^E2 is a conserved repressor of PV replication, whereas E4 is a late protein that arrests cells in G2 and collapses keratin filaments to facilitate virion release. While inactivation of the Mus musculus PV1 (MmuPV1) E8 start codon (E8-) increases viral gene expression, surprisingly, it prevents wart formation in FoxN1 nu/nu mice. To understand this surprising phenotype, the impact of additional E8^E2 mutations was characterized in tissue culture and mice. MmuPV1 and HPV E8^E2 similarly interact with cellular NCoR/SMRT-HDAC3 co-repressor complexes. Disruption of the splice donor sequence used to generate the E8^E2 transcript or E8^E2 mutants (mt) with impaired binding to NCoR/SMRT-HDAC3 activates MmuPV1 transcription in murine keratinocytes. These MmuPV1 E8^E2 mt genomes also fail to induce warts in mice. The phenotype of E8^E2 mt genomes in undifferentiated cells resembles productive PV replication in differentiated keratinocytes. Consistent with this, E8^E2 mt genomes induced aberrant E4 expression in undifferentiated keratinocytes. In line with observations for HPV, MmuPV1 E4-positive cells displayed a shift to the G2 phase of the cell cycle. In summary, we propose that in order to enable both expansion of infected cells and wart formation in vivo , MmuPV1 E8^E2 inhibits E4 protein expression in the basal keratinocytes that would otherwise undergo E4-mediated cell cycle arrest. IMPORTANCE Human papillomaviruses (PVs) initiate productive replication, which is characterized by genome amplification and expression of E4 protein strictly within suprabasal, differentiated keratinocytes. Mus musculus PV1 mutants that disrupt splicing of the E8^E2 transcript or abolish the interaction of E8^E2 with cellular NCoR/SMRT-HDAC3 co-repressor complexes display increased gene expression in tissue culture but are unable to form warts in vivo . This confirms that the repressor activity of E8^E2 is required for tumor formation and genetically defines a conserved E8 interaction domain. E8^E2 prevents expression of E4 protein in basal-like, undifferentiated keratinocytes and thereby their arrest in G2 phase. Since binding of E8^E2 to NCoR/SMRT-HDAC3 co-repressor is required to enable expansion of infected cells in the basal layer and wart formation in vivo , this interaction represents a novel, conserved, and potentially druggable target.

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Progression Pathways of Human Papillomavirus-Associated Cancer

Velázquez-Márquez,

Velez-Haro

2024

Pathogens Associated With the Development of Cancer in Humans

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Functions of Papillomavirus E8^E2 Proteins in Tissue Culture and In Vivo

Cited by 7 publications

References 81 publications

The human papillomavirus late life cycle and links to keratinocyte differentiation

The human papillomavirus late life cycle and links to keratinocyte differentiation

Mus musculus papillomavirus 1 E8^E2 represses expression of late protein E4 in basal-like keratinocytes via NCoR/SMRT-HDAC3 co-repressor complexes to enable wart formation in vivo

Progression Pathways of Human Papillomavirus-Associated Cancer

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