Human papillomavirus type 16 E6 and E 7 proteins alter NF-kB in cultured cervical epithelial cells and inhibition of NF-kB promotes cell growth and immortalization

Vandermark, Erik; Deluca, Krysta A.; Gardner, Courtney R.; Marker, Daniel F.; Schreiner, Cynthia; Strickland, David A.; Wilton, Katelynn M.; Mondal, Sumona; Woodworth, Craig D.

doi:10.1016/j.virol.2011.12.023

Cited by 94 publications

(91 citation statements)

References 48 publications

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“…HPV E6 and E7 proteins inhibit NF-B activity in cervical epithelial cells and downregulate expression of the interferon-responsive genes (27,28). Furthermore, HPV-16 E6 binds and inactivates IRF3, a major mediator of the interferon response; inhibits Toll-like receptor 9 activity (29); and interferes with PKR activation (30).…”

Section: G3bp1 and G3bp1-induced Sgs Restrict Enterovirus Infectionmentioning

confidence: 99%

The Stress Granule Protein G3BP1 Recruits Protein Kinase R To Promote Multiple Innate Immune Antiviral Responses

Reineke

Lloyd

2015

J Virol

181

189

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Stress granules (SGs) are cytoplasmic storage sites containing translationally silenced mRNPs that can be released to resume translation after stress subsides. We previously showed that poliovirus 3C proteinase cleaves the SG-nucleating protein G3BP1, blocking the ability of cells to form SGs late in infection. Many other viruses also target G3BP1 and inhibit SG formation, but the reasons why these functions evolved are unclear. Previously, we also showed a link between G3BP1-induced SGs and protein kinase R (PKR)-mediated translational control, but the mechanism of PKR interplay with SG and the antiviral consequences are unknown. Here, we show that G3BP1 exhibits antiviral activity against several enteroviruses, whereas truncated G3BP1 that cannot form SGs does not. G3BP1-induced SGs are linked to activation of innate immune transcriptional responses through NF-B and JNK. The G3BP1-induced SGs also recruit PKR and other antiviral proteins. We show that the PXXP domain within G3BP1 is essential for the recruitment of PKR to SGs, for eIF2␣ phosphorylation driven by PKR, and for nucleating SGs of normal composition. We also show that deletion of the PXXP domain in G3BP1 compromises its antiviral activity. These findings tie PKR activation to its recruitment to SGs by G3BP1 and indicate that G3BP1 promotes innate immune responses at both the transcriptional and translational levels and integrates cellular stress responses and innate immunity. IMPORTANCEStress granules appear during virus infection, and their importance is not well understood. Previously, it was assumed that they were nonfunctional artifacts associated with cellular stress. PKR is a well-known antiviral protein; however, its regulation in cells is not well understood. Our work links cellular stress granules with activation of PKR and other innate immune pathways through the activity of G3BP1, a critical stress granule component. The ability of stress granules and G3BP1 to activate PKR and other innate immune transcriptional responses indicates that G3BP1 is an antiviral protein. This work helps to refine a longstanding paradigm indicating stress granules are inert structures and explains why G3BP1 is subverted by many viruses to promote a productive infection. Stress granules (SGs) are macromolecular triage centers for mRNAs that contain translationally silenced messenger RNPs (mRNPs). Stress granules contain many translation initiation factors, 40S ribosomal subunits, mRNAs, and RNA-binding proteins, which form in response to cellular stresses that inhibit protein synthesis (1, 2). Stress responses are induced during virus infection and are countered by viruses to maximize replication efficiency. Indeed, several examples of viral SG disruption and viral subversion of SG proteins have been described (3-6), indicating stress granules may play antiviral roles against these viruses. Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) is a stress granule-resident protein that nucleates stress granule assembly and is also inactiv...

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Section: G3bp1 and G3bp1-induced Sgs Restrict Enterovirus Infectionmentioning

confidence: 99%

The Stress Granule Protein G3BP1 Recruits Protein Kinase R To Promote Multiple Innate Immune Antiviral Responses

Reineke

Lloyd

2015

J Virol

181

189

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“…E7 can suppress the activity of several key cellular tumor suppressors, such as pRb (34), NF-B (35,36), and p300 (37). An examination of the promoter of miR-145 revealed that p65 (Rel A), part of the NF-B transcriptional machinery, has two binding regions.…”

mentioning

confidence: 99%

“…An examination of the promoter of miR-145 revealed that p65 (Rel A), part of the NF-B transcriptional machinery, has two binding regions. E7 reduces NF-B activity in HPV-positive cells (35,36), and this may contribute to repression of miR-145 expression.…”

mentioning

confidence: 99%

Human Papillomaviruses Modulate MicroRNA 145 Expression To Directly Control Genome Amplification

Gunasekharan

Laimins

2013

J Virol

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H igh-risk human papillomaviruses (HPVs) are the causative agents of cervical and most other anogenital malignancies. Infection by HPVs occurs in the basal layers of stratified epithelia that become exposed due to microabrasions. Following entry, viral genomes are established as low-copy nuclear episomes at approximately 10 to 100 copies per cell (1, 2). In differentiated suprabasal layers, high levels of late gene expression are induced along with genome amplification and virion assembly (3). Two major viral promoters, designated early and late, control transcription during differentiation, but additional regulation also occurs through alternative splicing and other posttranscriptional mechanisms (1, 2, 4). One important mechanism of posttranscriptional control is mediated by small RNAs that are 22 nucleotides in size, referred to as microRNAs (miRNAs). miRNAs bind to partially complementary target sites in mRNA that are often located in the 3=UTR (untranslated regions) but can also be found in coding sequences and the 5=UTR (5). Binding by miRNAs to target sequences results in either the degradation of the target mRNAs or translational repression of the encoded protein (6). A single miRNA can repress the expression of over 100 genes, and a single gene can be repressed by multiple miRNAs. miRNAs often target multiple genes in a pathway and can act cooperatively with other miRNAs (7). Many miRNAs target developmental (8-10) and differentiation pathways (11)(12)(13)(14), as well as cell proliferation and transformation pathways (15-17). Herpesviruses and other small DNA viruses encode their own miRNAs (18); however, this is not the case for HPVs (19). Instead, HPVs modulate expression of host miRNAs to control various aspects of their viral life cycle (20, 21).Several miRNAs have been shown to be modulated by HPV proteins and to play key roles in the viral life cycle. miRNA 203 (miR-203) is a key regulator of epithelial differentiation and is downregulated in HPV-positive cells upon differentiation. This repression allows for the maintenance of high levels of p63, which is normally repressed by miR-203 in differentiating, infected suprabasal cells and is important for maintaining cells in an active state in the cell cycle (21). Additional studies demonstrated miR-218 to be downregulated by HPV E6, which correlates with increased levels of LAMB3, a translational target of this miRNA (22). A number of reports have documented changes in levels of cellular microRNAs in HPV-positive cells using microarray analyses, but only a limited number of studies has examined the significance of these changes in the viral life cycle (23-25).Since HPVs modulate the expression of cellular microRNAs to regulate aspects of their differentiation-dependent life cycle, we sought to identify cellular miRNAs that were altered by HPV proteins in a more physiological context than that reflected in monolayer cultures alone. For this analysis, we performed deep sequencing using organotypic raft cultures of a matched set of normal (viv) and H...

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“…Initially, E6 and E7 oncogenes suppress NF-kappaB in order to avoid the innate immune response and achieve the persistent infection. By establishing the persistence and chronic inflammation, they increase the activity of NF-kappaB signaling pathway that contributes to the development of cancer [9,10].…”

Section: Introductionmentioning

confidence: 99%

Cytokine genes polymorphisms of TNF, IFN-y and IL-12 as potential predictors in the onset of cervical disease associated with HR HPV infections

Tasic¹,

Pravica²,

Ćupić³

2015

Med podmladak

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Cervical cancer highly correlates with infection caused by highly oncogenic types of human papillomavirus (high risk HPV, HR HPV), which is one of the most common sexually transmitted pathogens and is a key factor in the development of cervical disease. However, malignant transformation of cells and tumor development are multifactorial and result from the interaction of a large number of factors such as virus genotype and its oncogenic potential, the state of the infected cells, the immune response of the host, as well as many cofactors such as smoking, oral contraceptives, multiparity, early beginning of sexual life, promiscuity, poor socio-economic conditions, poor diet, etc. Recently, an increasing number of studies have focused on examining the role of genetic basis of the pathogenesis and evolution of HR HPV cervical disease. It is known that genes polymorphisms that encode proteins involved in the functioning of Th1 and Th17 cell response may be associated with better or worse prognosis of cervical disease in women with persistent HR HPV infection. Therefore, the single nucleotide polymorphisms (SNP) of the genes encoding TNF, IFN-γ and IL-12 can be considered as putative biomarkers that may have predictive value for the development of the HR HPV cervical carcinoma.Key words: cervical cancer, HR HPV, gene polymorphism, TNF, IFN-γ and IL-12 Sažetak Karcinom grlića materice visoko korelira sa infekcijom uzrokovanom visoko onkogenim tipovima humanog papiloma virusa (engl. high risk HPV, HR HPV), koji je jedan od najčešće seksualno prenosivih patogena i ključni faktor u nastanku cervikalnog tumora. Ipak, maligna transformacija ćelija i nastanak tumora su multifaktorijalni i rezultat su interakcije velikog broja činilaca kao što su: genotip virusa i njegov onkogeni potencijal, stanje inficirane ćelije, imunskog odgovora domaćina, ali i brojnih kofaktora kao što su pušenje, oralni kontraceptivi, multiparitet, rano stupanje u seksualne odnose, promiskuitet, loši socioekonomski uslovi, ishrana i dr. U novije vreme sve veći broj istraživanja usmeren je na ispitivanje uloge genetske osnove u patogenezi i evoluciji HR HPV cervikalne bolesti. Poznato je da polimorfizmi određenih gena koji kodiraju proteine uključene u funkcionisanje Th1 i Th17 ćelijskog odgovora mogu biti povezani sa boljom ili lošijom prognozom cervikalne bolesti kod žena sa perzistentnom HR HPV infekcijom. Stoga se polimorfizmi pojedinačnih nukleotida (SNP) gena za TNF, IFN-γ i IL-12 mogu smatrati biomarkerima koji mogu da imaju prediktivnu ulogu za nastanak HR HPV karcinoma grlića materice.Ključne reči: karcinom grlića materice, genski polimorfizmi, TNF, IFN-γ i IL-12

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Human papillomavirus type 16 E6 and E 7 proteins alter NF-kB in cultured cervical epithelial cells and inhibition of NF-kB promotes cell growth and immortalization

Cited by 94 publications

References 48 publications

The Stress Granule Protein G3BP1 Recruits Protein Kinase R To Promote Multiple Innate Immune Antiviral Responses

The Stress Granule Protein G3BP1 Recruits Protein Kinase R To Promote Multiple Innate Immune Antiviral Responses

Human Papillomaviruses Modulate MicroRNA 145 Expression To Directly Control Genome Amplification

Cytokine genes polymorphisms of TNF, IFN-y and IL-12 as potential predictors in the onset of cervical disease associated with HR HPV infections

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