Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death

Singh, Nitu; Senapati, Sanjib; Bose, Kakoli

doi:10.1038/srep21408

Cited by 9 publications

(11 citation statements)

References 44 publications

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“…Overexpression of the E1^E4 proteins of HPV1, HPV16, or HPV18 induces a G 2 arrest in undifferentiated cells (38)(39)(40). In addition, HPV E2 proteins can also be growth inhibitory in both HPV-positive and -negative cells (7,41) and also induce cell death (42,43). It is thus possible that integration of HPV31 E8 2 genomes into host chromosomes is the result of a selection process to reduce viral gene expression to levels that can be tolerated by the infected cell.…”

Section: Discussionmentioning

confidence: 99%

Expression of E8^E2 Is Required for Wart Formation by Mouse Papillomavirus 1 In Vivo

Stubenrauch¹,

Straub²,

Klein³

et al. 2021

J Virol

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Human papillomavirus (HPV) E1 and E2 proteins activate genome replication. E2 also modulates viral gene expression and is involved in the segregation of viral genomes. In addition to full length E2, almost all PV share the ability to encode an E8^E2 protein, that is a fusion of E8 with the C-terminal half of E2 which mediates specific DNA-binding and dimerization. HPV E8^E2 acts as a repressor of viral gene expression and genome replication. To analyze the function of E8^E2 in vivo, we used the Mus musculus PV1 (MmuPV1)-mouse model system. Characterization of the MmuPV1 E8^E2 protein revealed that it inhibits transcription from viral promoters in the absence and presence of E1 and E2 proteins and that this is partially dependent upon the E8 domain. MmuPV1 genomes, in which the E8 ATG start codon was disrupted (E8-), displayed a 10- to 25-fold increase in viral gene expression compared to wt genomes in cultured normal mouse tail keratinocytes in short-term experiments. This suggests that the function and mechanism of E8^E2 is conserved between MmuPV1 and HPVs. Surprisingly, challenge of athymic nude Foxn1nu/nu mice with MmuPV1 E8- genomes did not induce warts on the tail in contrast to wt MmuPV1. Furthermore, viral gene expression was completely absent at E8- MmuPV1 sites 20 - 22 weeks after DNA challenge on the tail or quasivirus challenge in the vaginal vault. This reveals that expression of E8^E2 is necessary to form tumors in vivo and that this is independent from the presence of T-cells. IMPORTANCE HPV encode an E8^E2 protein which acts as repressors of viral gene expression and genome replication. In cultured normal keratinocytes, E8^E2 is essential for long-term episomal maintenance of HPV31 genomes, but not for HPV16. To understand E8^E2's role in vivo, the Mus musculus PV1 (MmuPV1)-mouse model system was used. This revealed that E8^E2's function as a repressor of viral gene expression is conserved. Surprisingly, MmuPV1 E8^E2 knock out genomes did not induce warts in T-cell deficient mice. This shows for the first time that expression of E8^E2 is necessary for tumor formation in vivo independently of T cell immunity. This indicates that E8^E2 could be an interesting target for anti-viral therapy in vivo.

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Section: Discussionmentioning

confidence: 99%

Expression of E8^E2 Is Required for Wart Formation by Mouse Papillomavirus 1 In Vivo

Stubenrauch¹,

Straub²,

Klein³

et al. 2021

J Virol

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“…On the other hand, some viral proteins can trigger caspase-8 activation through direct interactions. The high-risk human papillomavirus (HR-HPV) E2 protein can interact with procaspase-8 in a non-homotypic manner through its transactivation domain (TAD) with the DED-B of procaspase-8 [41]. This interaction drives DED oligomerization and triggers caspase-8 activation and the downstream apoptosis pathway [26,41].…”

Section: Modulation Of Extrinsic Apoptosis and Caspase-8 Activitymentioning

confidence: 99%

Regulation of innate immune responses by cell death‐associated caspases during virus infection

Fang

Peng

2021

The FEBS Journal

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Viruses are obligate intracellular pathogens that rely on cellular machinery for successful replication and dissemination. The host cells encode a number of different strategies to sense and restrict the invading viral pathogens. Caspase‐mediated programmed cell death pathways that are triggered by virus infection, such as apoptosis and pyroptosis, provide a means for the infected cells to limit viral proliferation, leading to suicidal cell death (apoptosis) or lytic cell death and alerting uninfected cells to mount anti‐viral responses (pyroptosis). However, some viruses can employ activated caspases to dampen the anti‐viral responses and facilitate viral replication through cleavage of critical molecules of the innate immune pathways. The regulation of innate immune responses by caspase activation during virus infection has recently become an important topic. In this review, we briefly introduce the characteristics of different classes of caspases and the cell death pathways regulated by these caspases. We then describe how viruses trigger or dampen caspase activation during infection and how these activated caspases regulate three major innate immune response pathways of viral infections: the retinoic acid‐inducible gene I‐like receptor, toll‐like receptor and cyclic GMP‐AMP synthase‐stimulator of interferon genes pathways.

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“…Disruption of this complex epigenetic control mechanism can affect the structure and the integrity of the genome and alter the expression of genes critically involved in tumorigenesis. Of note, it has becoming increasingly clear that environmental and lifestyle risk factors can promote a wide range of epigenetic alterations that are causally involved in cancer development and progression [ 17 ]. Based on these considerations, the primary objective of this review is to resume the common epigenetic events in OPSCC and to discuss their potential translational applications for the management of this disease.…”

Section: Introductionmentioning

confidence: 99%

Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors

et al. 2017

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In the last years, the explosion of high throughput sequencing technologies has enabled epigenome-wide analyses, allowing a more comprehensive overview of the oropharyngeal squamous cell carcinoma (OPSCC) epigenetic landscape. In this setting, the cellular pathways contributing to the neoplastic phenotype, including cell cycle regulation, cell signaling, DNA repair, and apoptosis have been demonstrated to be potential targets of epigenetic alterations in OPSCC. Of note, it has becoming increasingly clear that HPV infection and OPSCC lifestyle risk factors differently drive the epigenetic machinery in cancer cells. Epigenetic changes, including DNA methylation, histone modifications, and non-coding RNA expression, can be used as powerful and reliable tools for early diagnosis of OPSCC patients and improve prognostication. Since epigenetic changes are dynamic and reversible, epigenetic enzymes may also represent suitable targets for the development of more effective OPSCC therapeutic strategies. Thus, this review will focus on the main known epigenetic modifications that can occur in OPSCC and their exploitation as potential biomarkers and therapeutic targets. Furthermore, we will address epigenetic alterations to OPSCC risk factors, with a particular focus on HPV infection, tobacco exposure, and heavy alcohol consumption.

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Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death

Cited by 9 publications

References 44 publications

Expression of E8^E2 Is Required for Wart Formation by Mouse Papillomavirus 1 In Vivo

Expression of E8^E2 Is Required for Wart Formation by Mouse Papillomavirus 1 In Vivo

Regulation of innate immune responses by cell death‐associated caspases during virus infection

Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors

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