Persistence of an Oncogenic Papillomavirus Genome Requires
            <i>cis</i>
            Elements from the Viral Transcriptional Enhancer

Doorslaer, Koenraad Van; Chen, Dan; Chapman, Sandra; Khan, Jameela; McBride, Alison A.

doi:10.1128/mbio.01758-17

Cited by 15 publications

(20 citation statements)

References 40 publications

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“…To create a feeder layer to support the growth of primary human foreskin keratinocytes, J2 fibroblasts were irradiated every 3–4 days. Cells were removed from continuing culture flasks, resuspended in media in a 15 mL conical, and irradiated with 6000 rads using a Gammacell 40 cesium-137 source as described [ 136 ]. Irradiated cells were plated at 1 million cells per 10 cm plate to later be used for support of primary keratinocytes.…”

Section: Methodsmentioning

confidence: 99%

Vesicular trafficking permits evasion of cGAS/STING surveillance during initial human papillomavirus infection

Uhlorn

Jackson

et al. 2020

PLoS Pathog

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Oncogenic human papillomaviruses (HPVs) replicate in differentiating epithelium, causing 5% of cancers worldwide. Like most other DNA viruses, HPV infection initiates after trafficking viral genome (vDNA) to host cell nuclei. Cells possess innate surveillance pathways to detect microbial components or physiological stresses often associated with microbial infections. One of these pathways, cGAS/STING, induces IRF3-dependent antiviral interferon (IFN) responses upon detection of cytosolic DNA. Virion-associated vDNA can activate cGAS/STING during initial viral entry and uncoating/trafficking, and thus cGAS/STING is an obstacle to many DNA viruses. HPV has a unique vesicular trafficking pathway compared to many other DNA viruses. As the capsid uncoats within acidic endosomal compartments, minor capsid protein L2 protrudes across vesicular membranes to facilitate transport of vDNA to the Golgi. L2/vDNA resides within the Golgi lumen until G2/M, whereupon vesicular L2/vDNA traffics along spindle microtubules, tethering to chromosomes to access daughter cell nuclei. L2/vDNA-containing vesicles likely remain intact until G1, following nuclear envelope reformation. We hypothesize that this unique vesicular trafficking protects HPV from cGAS/STING surveillance. Here, we investigate cGAS/STING responses to HPV infection. DNA transfection resulted in acute cGAS/STING activation and downstream IFN responses. In contrast, HPV infection elicited minimal cGAS/STING and IFN responses. To determine the role of vesicular trafficking in cGAS/STING evasion, we forced premature viral penetration of vesicular membranes with membrane-perturbing cationic lipids. Such treatment renders a non-infectious trafficking-defective mutant HPV infectious, yet susceptible to cGAS/STING detection. Overall, HPV evades cGAS/STING by its unique subcellular trafficking, a property that may contribute to establishment of infection.

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Section: Methodsmentioning

confidence: 99%

Vesicular trafficking permits evasion of cGAS/STING surveillance during initial human papillomavirus infection

Uhlorn

Jackson

et al. 2020

PLoS Pathog

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“…In a plasmid retention assay, two HPV18 E2BS from the origin were sufficient to maintain non-replicating plasmids in dividing cells [ 61 ], further supporting the role of the E2 protein in this process. In keratinocytes, HPV18-derived replicons complemented in trans by the entire HPV18 genome required only the minimal replication origin (with three E2BS) and sequences from the transcriptional enhancer (designated the minichromosome maintenance enhancer element (MMEE) [ 62 ]. Therefore, while the E2 tethering model still holds, it is likely mediated by complexes of the viral E2 protein and cellular factors associated with the viral genome.…”

Section: Papillomavirus Genome Replicationmentioning

confidence: 99%

Persistent Human Papillomavirus Infection

Fera

Warburton

Coursey

et al. 2021

Viruses

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106

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Persistent infection with oncogenic human papillomavirus (HPV) types is responsible for ~5% of human cancers. The HPV infectious cycle can sustain long-term infection in stratified epithelia because viral DNA is maintained as low copy number extrachromosomal plasmids in the dividing basal cells of a lesion, while progeny viral genomes are amplified to large numbers in differentiated superficial cells. The viral E1 and E2 proteins initiate viral DNA replication and maintain and partition viral genomes, in concert with the cellular replication machinery. Additionally, the E5, E6, and E7 proteins are required to evade host immune responses and to produce a cellular environment that supports viral DNA replication. An unfortunate consequence of the manipulation of cellular proliferation and differentiation is that cells become at high risk for carcinogenesis.

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“…On the other hand, re-expression of MYPOP might result in reduced cell growth. We therefore overexpressed MYPOP in HPV-transformed SiHa and HeLa cells and tested arrest of proliferation in microscopy analyses or standard quantitative colony formation assays, as described previously [ 56 , 57 ]. Indeed, MYPOP-GFP-expressing cells displayed altered cell morphology and no tendency to form colonies (Suppl.…”

Section: Resultsmentioning

confidence: 99%

The Myb-related protein MYPOP is a novel intrinsic host restriction factor of oncogenic human papillomaviruses

et al. 2018

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The skin represents a physical and chemical barrier against invading pathogens, which is additionally supported by restriction factors that provide intrinsic cellular immunity. These factors detect viruses to block their replication cycle. Here, we uncover the Myb-related transcription factor, partner of profilin (MYPOP) as a novel antiviral protein. It is highly expressed in the epithelium and binds to the minor capsid protein L2 and the DNA of human papillomaviruses (HPV), which are the primary causative agents of cervical cancer and other tumors. The early promoter activity and early gene expression of the oncogenic HPV types 16 and 18 is potently silenced by MYPOP. Cellular MYPOP-depletion relieves the restriction of HPV16 infection, demonstrating that MYPOP acts as a restriction factor. Interestingly, we found that MYPOP protein levels are significantly reduced in diverse HPV-transformed cell lines and in HPV-induced cervical cancer. Decades ago it became clear that the early oncoproteins E6 and E7 cooperate to immortalize keratinocytes by promoting degradation of tumor suppressor proteins. Our findings suggest that E7 stimulates MYPOP degradation. Moreover, overexpression of MYPOP blocks colony formation of HPV and non-virally transformed keratinocytes, suggesting that MYPOP exhibits tumor suppressor properties.

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Persistence of an Oncogenic Papillomavirus Genome Requires cis Elements from the Viral Transcriptional Enhancer

Cited by 15 publications

References 40 publications

Vesicular trafficking permits evasion of cGAS/STING surveillance during initial human papillomavirus infection

Vesicular trafficking permits evasion of cGAS/STING surveillance during initial human papillomavirus infection

Persistent Human Papillomavirus Infection

The Myb-related protein MYPOP is a novel intrinsic host restriction factor of oncogenic human papillomaviruses

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