The PP4R1 sub-unit of protein phosphatase PP4 is essential for inhibition of NF-κB by merkel polyomavirus small tumour antigen

Abdul-Sada, Hussein; Müller, Marietta; Mehta, Rajni; Toth, Rachel; Arthur, J. Simon C.; Whitehouse, Adrian; Macdonald, Andrew

doi:10.18632/oncotarget.15836

Cited by 37 publications

(43 citation statements)

References 45 publications

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“…Cells were transfected with 180 ng of reporter plasmid expressing a Firefly luciferase under the control of an NF-κB sensitive promoter as previously described 27 , alongside 20 ng of transfection control pRL-TK (Promega) using Lipofectamine 2000 (Life Technologies). Luciferase samples were collected and quantified using the Dual Luciferase reporter assay system (Promega).…”

Section: Methodsmentioning

confidence: 99%

The Chikungunya virus nsP3 macro domain inhibits activation of the NF-κB pathway

Roberts

Stonehouse

Harris

2019

Preprint

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14The role of the chikungunya virus (CHIKV) non-structural protein 3 (nsP3) in the virus lifecycle 15 is poorly understood. The protein comprises 3 domains. The N-terminus is a macro domain, 16 biochemically characterised to bind both RNA and ADP-ribose, and to possess ADP-ribosyl 17 hydrolase activity -an enzymatic activity that removes ADP-ribose from mono-ADP-18 ribosylated proteins. As ADP-ribosylation is important in the signalling pathway leading to 19 activation of the transcription factor NF-кB, we sought to determine if the macro domain might 20 perturb NF-кB signalling. We first show that CHIKV infection did not induce NF-кB activation, 21 and could not block exogenous activation of the pathway via TNFα, although TNFα treatment 22 did reduce virus titres. Ectopic expression of nsP3 was able to block TNFα-mediated NF-кB 23 activation and this was dependent on the macro domain, as mutations previously shown to 24 disrupt either ADP-ribose binding or hydrolase activity lost the ability to inhibit NF-кB 25 activation. Lastly, we determined the phenotype of the macro domain mutants in the context 26 of virus infection in a range of cell types. Our data are consistent with cell-and species-27 dependent roles of the macro domain, however, these phenotypes do not correlate with the 28 ability to inhibit NF-кB activation suggesting that the macro domain plays multiple independent 29 roles in the virus lifecycle.Chikungunya virus (CHIKV) is an alphavirus of the Togaviridae family, and is increasingly 32 becoming a threat to global health. First discovered in Tanzania in 1952, CHIKV is now 33 classified into four distinct genotypes and has spread from Africa to Asia, Europe, and the 34 Americas 1 . CHIKV is transmitted by mosquitos and was previously geographically limited to 35 the distribution of the Aedes aegypti mosquito which favours tropical climates. However, 36 mutations in the E1 and E2 glycoproteins, detected in 2004, have enabled spread by the 37Aedes albopictus mosquito, which is more widely disseminated around the globe 2 . 38Infection with CHIKV causes Chikungunya fever, characterised by high fever, rash and joint 39 pain which can be debilitating and, in some cases, persistent 3 . CHIKV infection induces a 40 highly inflammatory state, inducing tissue damage 4 . In addition, individuals who have been 41 infected with CHIKV are significantly predisposed to arthritis in later life 5 . In healthy adults, 42 CHIKV is rarely fatal though the risk of death is high in infants, the elderly and the 43 immunocompromised 6 . 44The CHIKV genome is a positive-sense, single stranded (ss) RNA. It possesses a 5' cap and 45 a poly-A tail and contains two open reading frames (ORFs) 7 . The first ORF encodes for the 46 four non-structural proteins, nsP1-4, which are directly translated from the genomic RNA 8 . The 47 NF-кB pathway, and is unable to suppress exogenous activation of the pathway via TNFα 84 treatment. However, in contrast we further demonstrate that ectopic expression of nsP3 is 85 able to inhibit exogen...

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Section: Methodsmentioning

confidence: 99%

The Chikungunya virus nsP3 macro domain inhibits activation of the NF-κB pathway

Roberts

Stonehouse

Harris

2019

Preprint

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“…Binding of st-ag to this protein leads to stabilization of SCF Fbw7 substrates such as LT-ag, cMyc, and cyclin E and this can contribute to carcinogenesis [reviewed in 6 ]. Furthermore, the interaction with the eukaryotic translation regulator 4E-BP1 and the protein phosphatase 4 affects cellular translation and NF-κB-dependent transcription, respectively, and may also play a role in MCPyV-induced MCC [6,8,9] .…”

Section: Objectivementioning

confidence: 99%

Detection of Merkel Cell Polyomavirus in Respiratory Tract Specimens

Shikova

Emin²,

Alexandrova³

et al. 2017

Intervirology

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Objective: The role of Merkel cell polyomavirus (MCPyV) as a respiratory pathogen is controversial. The aim of this study was to determine the prevalence of MCPyV in patients with acute respiratory diseases and chronic lung diseases, including lung cancer, in order to evaluate the association between MCPyV infection and respiratory diseases. Methods: This study included 221 specimens (133 nasopharyngeal swabs and 88 lung biopsy specimens) obtained from patients with acute respiratory diseases and chronic lung diseases, including lung cancer. The detection of MCPyV was performed via nested polymerase chain reaction. Results: MCPyV positivity was 4.3% on average. All nasopharyngeal specimens were obtained from patients with acute respiratory diseases, and 8.2% of them were MCPyV DNA positive. There were no statistically significant differences in MCPyV prevalence according to age or gender. All specimens from nonmalignant chronic lung diseases and lung cancer were MCPyV negative. Conclusions: MCPyV was observed in specimens from patients with acute respiratory diseases, indicating that there may be a relationship between the virus and these diseases. We were not able to detect MCPyV in samples from patients with chronic lung diseases, including lung cancer, suggesting no association with MCPyV infection and no involvement of this polyomavirus in lung cancerogenesis.

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“…Assays were performed as previously described (72). Briefly, cells were transfected with FLAG-USP13, pcDNA3.1-V5-hMcl-1 or both.…”

Section: Immunoprecipitationsmentioning

confidence: 99%

The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer

Morgan

Patterson

Barba-Moreno

et al. 2020

Preprint

Self Cite

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Ubiquitination is a critical regulator of cellular homeostasis. Aberrations in the addition or removal of ubiquitin can result in the development of cancer and key components of the ubiquitination machinery serve as oncogenes or tumour suppressors. An emerging target in the development of cancer therapeutics are the deubiquitinase (DUB) enzymes that remove ubiquitin from protein substrates. Whether this class of enzyme plays a role in cervical cancer has not been fully explored. By interrogating the cervical cancer data from the TCGA consortium, we noted that the DUB USP13 is amplified in approximately 15% of cervical cancer cases. We confirmed that USP13 expression was increased in cervical cancer cell lines, cytology samples from patients with cervical disease and in cervical cancer tissue. Depletion of USP13 inhibited cervical cancer cell proliferation. Mechanistically, USP13 bound to, deubiquitinated and stabilised Mcl-1, a pivotal member of the anti-apoptotic Bcl-2 family and the reduced Mcl-1 expression contributed to the observed proliferative defect. Importantly, the expression of USP13 and Mcl-1 proteins correlated in cervical cancer tissue. Finally, we demonstrated that depletion of USP13 expression or inhibition of USP13 enzymatic activity increased the sensitivity of cervical cancer cells to the BH3 mimetic inhibitor ABT-263. Together, our data demonstrates that USP13 is a potential oncogene in cervical cancer that functions to stabilise the pro-survival protein Mcl-1, offering a potential therapeutic target for these cancers.

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The PP4R1 sub-unit of protein phosphatase PP4 is essential for inhibition of NF-κB by merkel polyomavirus small tumour antigen

Cited by 37 publications

References 45 publications

The Chikungunya virus nsP3 macro domain inhibits activation of the NF-κB pathway

The Chikungunya virus nsP3 macro domain inhibits activation of the NF-κB pathway

Detection of Merkel Cell Polyomavirus in Respiratory Tract Specimens

The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer

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