Expression of Signaling Molecules in Progressive Multifocal Leukoencephalopathy

Wollebo, Hassen S.; Cotto, Bianca; Adiga, Radhika; Langford, Dianne; White, Martyn K.

doi:10.2174/1570162x1401151102125319

Cited by 8 publications

(6 citation statements)

References 33 publications

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“…In another study, evaluation of HIV‐1/PML clinical samples and non‐PML controls for expression of TNF‐α and its receptor TNFR1 showed an increase in overall expression in PML as measured by western blot and specific induction in bizarre astrocytes and enlarged oligodendrocytes measured by immunohistochemistry as well as a redistribution of the transcription factors NF‐κB and NFAT4 to preferential localization to the nucleus. This is consistent with the activation of this cytokine/transcription factor pathway in PML .…”

Section: Tests Involving Assays On Biopsy or Autopsy Materialssupporting

confidence: 90%

Diagnostic assays for polyomavirus JC and progressive multifocal leukoencephalopathy

White

Sariyer

Gordon

et al. 2015

Reviews in Medical Virology

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SUMMARY Progressive multifocal leukoencephalopathy (PML) is a devastating and often fatal demyelinating disease of the central nervous system (CNS) for which effective therapies are lacking. It is caused by the replication of polyomavirus JC (JCV) in the oligodendrocytes and astrocytes leading to their cytolytic death and loss of myelin from the subcortical white matter. While the virus is very common in human populations worldwide, the incidence of the disease is very low and confined almost exclusively to individuals with some form of immunological dysfunction. However, the number of people who constitute the at-risk population is growing larger and includes individuals with HIV-1/AIDS and patients receiving immunomodulatory therapies such as multiple sclerosis patients treated with natalizumab. Further adding to the public health significance of this disease are the difficulties encountered in the diagnosis of PML and the lack of useful biomarkers for PML progression. In this review, we examine the diagnostic assays that are available for different aspects of the JCV life cycle, their usefulness and drawbacks, and the prospects for improvements.

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Section: Tests Involving Assays On Biopsy or Autopsy Materialssupporting

confidence: 90%

Diagnostic assays for polyomavirus JC and progressive multifocal leukoencephalopathy

White

Sariyer

Gordon

et al. 2015

Reviews in Medical Virology

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“…We have proposed that proinflammatory cytokines such as those that occur in HIV-1/AIDS reactivate JCV leading to PML (White and Khalili 2011). In support of this, we found that TNF-α and its receptor TNFR1 are upregulated in clinical samples from HIV/PML and immunohistochemistry of PML brain tissue shows redistribution of NF-κB to the nucleus (Wollebo et al 2016). …”

Section: Introductionsupporting

confidence: 54%

“…Due to its many interactions with other proteins, this JCV NF-κB site also constitutes a nexus for JCV regulation by other signaling pathways including the DNA damage response (White et al 2014) and calcium-activated signaling (Wollebo et al 2012), which are mediated by direct interaction of NF-κB p65 with the proteins Rad51 and NFAT4 respectively. The pathological relevance of these proteins is indicated by the observations that Rad51 is barely detectable in normal brain but is robustly induced in HIV/PML brain sections (Darbinyan et al 2007) and that NFAT4 preferentially localizes to the nuclei of oligodendrocytes and bizarre astrocytes in HIV/PML relative to what is observed in non-PML brain sections (Wollebo et al 2016). A further level of complexity is added to this by the finding that NF-κB p65 is subject to epigenetic regulation of its stimulatory effect on JCV activity by acetylation.…”

Section: Discussionmentioning

confidence: 99%

The Brd4 acetyllysine-binding protein is involved in activation of polyomavirus JC

et al. 2016

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Brd4 is an epigenetic reader protein and a member of the BET (bromodomain and extra terminal domain) family of proteins with two bromodomains that recognize acetylated lysine residues. Brd4 specifically binds to acetylated transcription factor NF-κB p65 and coactivates transcription. Polyomavirus JC (JCV) is regulated by a noncoding control region (NCCR) containing promoter/enhancer elements for viral gene expression including a binding site for NF-κB, which responds to proinflammatory cytokines such as TNF-α, the DNA damage response, calcium signaling and acetylation of the NF-κB p65 subunit on lysine residues K218 and K221. Earlier studies indicated that NF-κB is involved in the reactivation of persistent/latent JCV in glial cells to cause progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the brain caused by replication of JCV in glial cells. To investigate the mechanism of action of NF-κB acetylation on JCV transcription, we examined Brd4 and found that JCV early transcription was stimulated by Brd4 via the JCV NF-κB site and that p65 K218 and K221 were involved. Treatment with the Brd4 inhibitor JQ1(+) or mutation of either K218 or K221 to glutamine (K218R or K221) inhibited this stimulation and decreased the proportion of p65 in the nucleus. We conclude that Brd4 is involved in the regulation of the activation status of JCV in glial cells.

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“…From earlier studies, it is known that active NF-κB translocation to the nucleus [ 45 , 46 ] stimulates transcription of NF-κB-dependent genes including both the early and late genes of JCV as described in our earlier studies [ 13 – 18 , 35 , 36 ]. JCV infection-induced DDR signaling is associated with a large elevation in the expression level of Rad51 protein [ 19 ], which then physically associates with NF-κB and augment its function [ 23 ] and stimulate transcription of JCV early gene expression [ 17 ].…”

Section: Discussionmentioning

confidence: 86%

“…Cells were harvested as we have described [ 13 , 33 , 34 ] except for experiments to measure sumoylation where iodoacetemide (10 mM) was added to the lysis and wash buffers to preserve SUMOylation. Western blots were performed as described [ 33 , 35 , 36 ]. Briefly, 50 μg of protein was resolved by SDS-PAGE, transferred to nitrocellulose, and immunoblotted with primary antibody (1/1000 dilution) and secondary antibody (1/10000 dilution).…”

Section: Methodsmentioning

confidence: 99%

The DNA damage response promotes polyomavirus JC infection by nucleus to cytoplasm NF- kappaB activation

White

Bellizzi

Ibba

et al. 2017

Virol J

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BackgroundInfection of glial cells by human neurotropic polyomavirus JC (JCV), the causative agent of the CNS demyelinating disease progressive multifocal leukoencephalopathy (PML), rapidly inflicts damage to cellular DNA. This activates DNA damage response (DDR) signaling including induction of expression of DNA repair factor Rad51. We previously reported that Rad51 co-operates with the transcription factor NF-κB p65 to activate JCV early transcription. Thus Rad51 induction by JCV infection may provide positive feedback for viral activation early in JCV infection. DDR is also known to stimulate NF-κB activity, a phenomenon known as nucleus to cytoplasm or “inside-out” NF-κB signaling, which is initiated by Ataxia telangiectasia mutated (ATM) protein, a serine/threonine kinase recruited and activated by DNA double-strand breaks. Downstream of ATM, there occurs a series of post-translational modifications of NF-κB essential modulator (NEMO), the γ regulatory subunit of inhibitor of NF-κB (IκB) kinase (IKK), resulting in NF-κB activation.MethodsWe analyzed the effects of downstream pathways in the DDR by phosphospecific Western blots and analysis of the subcellular distribution of NEMO by cell fractionation and immunocytochemistry. The role of DDR in JCV infection was analyzed using a small molecule inhibitor of ATM (KU-55933). NEMO sumoylation was investigated by Western and association of ATM and NEMO by immunoprecipitation/Western blots.ResultsWe show that JCV infection caused phosphorylation and activation of ATM while KU-55933 inhibited JCV replication. JCV infection caused a redistribution of NEMO from cytoplasm to nucleus. Co-expression of JCV large T-antigen and FLAG-tagged NEMO showed the occurrence of sumoylation of NEMO, while co-expression of ATM and FLAG-NEMO demonstrated physical association between ATM and NEMO.ConclusionsWe propose a model where JCV infection induces both overexpression of Rad51 protein and activation of the nucleus to cytoplasm NF-κB signaling pathway, which then act together to enhance JCV gene expression.

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Expression of Signaling Molecules in Progressive Multifocal Leukoencephalopathy

Cited by 8 publications

References 33 publications

Diagnostic assays for polyomavirus JC and progressive multifocal leukoencephalopathy

Diagnostic assays for polyomavirus JC and progressive multifocal leukoencephalopathy

The Brd4 acetyllysine-binding protein is involved in activation of polyomavirus JC

The DNA damage response promotes polyomavirus JC infection by nucleus to cytoplasm NF- kappaB activation

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