Human papillomavirus type 16 E6 and NFX1-123 mislocalize immune signaling proteins and downregulate immune gene expression in keratinocytes

Levan, Justine; Vliet-Gregg, Portia A.; Robinson, Kristin; Katzenellenbogen, Rachel A.

doi:10.1371/journal.pone.0187514

Cited by 11 publications

(10 citation statements)

References 52 publications

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“…Both inhibitors of B alpha and beta (IB-alpha and IB-beta) were increased by HPV16. We also observed the decrease of the Rel and p100/p52 NF-B subunits by HPV16, which is also consistent with suppression of NF-B activity by HPV oncogenes reported in some previous studies (83)(84)(85)(86)(87)(88)(89)(90)(91)(92). STAT1 Y701 phosphorylation was also reduced, further confirming the observations shown in Fig.…”

Section: Resultssupporting

confidence: 92%

Human Papillomavirus 16 E5 Inhibits Interferon Signaling and Supports Episomal Viral Maintenance

Scott

Woodby

Ulicny

et al. 2020

J Virol

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Human papillomaviruses (HPVs) infect keratinocytes of stratified epithelia. Long-term persistence of infection is a critical risk factor for the development of HPV-induced malignancies. Through the actions of its oncogenes, HPV evades host immune responses to facilitate its productive life cycle. In this work, we discovered a previously unknown function of the HPV16 E5 oncoprotein in the suppression of interferon (IFN) responses. This suppression is focused on keratinocyte-specific IFN-κ and is mediated through E5-induced changes in growth factor signaling pathways, as identified through phosphoproteomics analysis. The loss of E5 in keratinocytes maintaining the complete HPV16 genome results in the derepression of IFNK transcription and subsequent JAK/STAT-dependent upregulation of several IFN-stimulated genes (ISGs) at both the mRNA and protein levels. We also established a link between the loss of E5 and the subsequent loss of genome maintenance and stability, resulting in increased genome integration. IMPORTANCE Persistent human papillomavirus infections can cause a variety of significant cancers. The ability of HPV to persist depends on evasion of the host immune system. In this study, we show that the HPV16 E5 protein can suppress an important aspect of the host immune response. In addition, we find that the E5 protein is important for helping the virus avoid integration into the host genome, which is a frequent step along the pathway to cancer development.

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Section: Resultssupporting

confidence: 92%

Human Papillomavirus 16 E5 Inhibits Interferon Signaling and Supports Episomal Viral Maintenance

Scott

Woodby

Ulicny

et al. 2020

J Virol

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“…Two studies have highlighted the collaborative role NFX1 plays in immune regulation by HR HPV. In one, whole-genome microarray analysis of keratinocytes stably expressing 16E6 and a tagged overexpressed form of NFX1-123 revealed the downregulation of pro-inflammatory cytokines and interferon-stimulated genes at mRNA and protein levels, indicating the requirement of NFX1-123 for immune regulation by HPV [ 44 ]. In a second, immunogenic epitopes of HR HPV type 45, analyzed by time core simulation, revealed an overlap between the antigenicity of HR HPV proteins and epitopes from several endogenous cellular proteins; NFX1 was included as one of many proteins and pathways that contained overlapping epitopes [ 45 ].…”

Section: Nfx1 and Nfxl1 Functions In Human Diseasesmentioning

confidence: 99%

NFX1, Its Isoforms and Roles in Biology, Disease and Cancer

Chintala

Katzenellenbogen

2021

Biology

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In 1989, two NFX1 protein products were identified as nuclear proteins with the ability to bind to X-box cis-elements. Since that publication, the NFX1 gene and its homologs have been identified, from yeast to humans. This review article summarizes what is known about the NFX1 gene across species. We describe the gene and protein motifs of NFX1 homologs and their functions in cellular biology, then turn to NFX1 in human biology and disease development. In that, we focus on more recent literature about NFX1 and its two splice variants protein products (NFX1-91 and NFX1-123) that are expressed in epithelial cells. We describe new evidence of conserved protein motifs, direct and indirect gene expression regulation, and critical protein-protein interactions. Finally, we stress the emerging roles of these NFX1 splice variants in high-risk human papillomavirus-associated cancers, and the increased expression of the longer splice variant, NFX1-123, found in these cancers.

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“…Following our observation that NFX1-123 protein expression, as well as NFX1 mRNA levels, were increased in cervical cancers (Figures 1 and 2), and knowing that 16E6 and NFX1-123 increased a wide range of genes and regulated several cellular pathways in HFKs, 24,25,31 we chose to investigate if these same genes were also increased in cervical tumors. We returned to the TCGA Target GTEx database to examine mRNA expression of genes shown to be upregulated twofold or more in HFKs with 16E6 and overexpressed NFX1-123.…”

Section: Nfx1-123 Proliferation Markers and Differentiation Markers Were Highly Expressed In Cervical Cancer Specimensmentioning

confidence: 99%

<p>Genes Regulated by HPV 16 E6 and High Expression of NFX1-123 in Cervical Cancers</p>

Chintala¹,

Levan²,

Robinson³

et al. 2020

OTT

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High-risk human papillomaviruses (HR HPV) cause cervical cancer, and in these cancers, HPV type 16 is the most common HR type. The HR viral oncogenes E6 and E7 partner with cellular proteins to drive cancer and modulate immune pathways; previously, we demonstrated in keratinocytes that HPV 16 E6 and high expression of the endogenous host protein partner NFX1-123 led to the increased expression of multiple genes, including Notch1, secretory leukocyte peptidase inhibitor (SLPI), and retinoic acid early transcript 1G (RAET1G). The present study was conducted to determine if NFX1-123 was highly expressed in cervical cancer and if genes increased by NFX1-123 and 16E6 in keratinocytes were also increased in cervical cancers. Materials and Methods: The Cancer Genome Atlas (TCGA) database and The Human Protein Atlas database were used to compare relative mRNA and protein gene expression, respectively, in the normal cervix and cervical cancers. Formalin-fixed paraffin-embedded (FFPE) normal cervix and HPV 16 positive cervical cancer samples were analyzed for relative protein expression by immunohistochemical staining. Protein expression of a subset of regulated genes was quantified by Western blot of HPV positive and negative cell lines. Results: Immunohistochemical staining of HPV 16 positive cervical dysplasias and cancers revealed high NFX1-123, Ki67, and Notch1 expression. NFX1 and NFX1L1 mRNA levels were increased in cervical cancers compared to normal cervix in the TCGA database. Fourteen genes previously identified as upregulated in keratinocytes with 16E6 and overexpressed NFX1-123 also had high mRNA expression and selected genes had high protein expression in cervical cancers and cell lines. Conclusion: In cervical cancer, NFX1-123 is highly expressed, and 16E6 and NFX1-123 together alter the expression of a wide set of genes. The involvement of these genes in cell proliferation, differentiation, invasion, and metastasis provides further insight into potential ways that HR HPVs promote cancer initiation and maintenance.

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Human papillomavirus type 16 E6 and NFX1-123 mislocalize immune signaling proteins and downregulate immune gene expression in keratinocytes

Cited by 11 publications

References 52 publications

Human Papillomavirus 16 E5 Inhibits Interferon Signaling and Supports Episomal Viral Maintenance

Human Papillomavirus 16 E5 Inhibits Interferon Signaling and Supports Episomal Viral Maintenance

NFX1, Its Isoforms and Roles in Biology, Disease and Cancer

<p>Genes Regulated by HPV 16 E6 and High Expression of NFX1-123 in Cervical Cancers</p>

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