Tumor suppressor p53 functions as an essential antiviral molecule against Japanese encephalitis virus

Deng, Xunming; Wei, Jianchao; Shi, Zhu‐Pei; Yan, Wenjun; Wu, Zhonghu; Shao, Donghua; Li, Beibei; Liu, Ke; Wang, Xiaodu; Qiu, Yafeng; Ma, Zhiyong

doi:10.1016/j.jgg.2016.07.002

Cited by 8 publications

(12 citation statements)

References 19 publications

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“…Investigations on the association between the anti‐cancer activity of HSP90 inhibitors and their anti‐inflammatory properties have forged a strong body of evidence which not only supports the anti‐inflammatory activity of HSP90 inhibitors in the vasculature, but has specifically revealed a protective action against bacterial‐induced vascular hyper‐permeability . One of the many client proteins of HSP90 which are involved in cellular stability is the transcription factor and “guardian of the genome,” P53 . In a series of independent studies , p53 has been demonstrated to exert both anti‐cancer and anti‐inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

Wild‐type p53 enhances endothelial barrier function by mediating RAC1 signalling and RhoA inhibition

Barabutis

Dimitropoulou

Gregory

et al. 2018

J Cellular Molecular Medi

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Inflammation is the major cause of endothelial barrier hyper‐permeability, associated with acute lung injury and acute respiratory distress syndrome. This study reports that p53 “orchestrates” the defence of vascular endothelium against LPS, by mediating the opposing actions of Rac1 and RhoA in pulmonary tissues. Human lung microvascular endothelial cells treated with HSP90 inhibitors activated both Rac1‐ and P21‐activated kinase, which is an essential element of vascular barrier function. 17AAG increased the phosphorylation of both LIMK and cofilin, in contrast to LPS which counteracted those effects. Mouse lung microvascular endothelial cells exposed to LPS exhibited decreased expression of phospho‐cofilin. 17AAG treatment resulted in reduced levels of active cofilin. Silencing of cofilin pyridoxal phosphate phosphatase (PDXP) blocked the LPS‐induced hyper‐permeability, and P53 inhibition reversed the 17AAG‐induced PDXP down‐regulation. P190RHOGAP suppression enhanced the LPS‐triggered barrier dysfunction in endothelial monolayers. 17AAG treatment resulted in P190RHOGAP induction and blocked the LPS‐induced pMLC2 up‐regulation in wild‐type mice. Pulmonary endothelial cells from “super p53” mice, which carry additional p53‐tg alleles, exhibited a lower response to LPS than the controls. Collectively, our findings help elucidate the mechanisms by which p53 operates to enhance barrier function.

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Section: Discussionmentioning

confidence: 99%

Wild‐type p53 enhances endothelial barrier function by mediating RAC1 signalling and RhoA inhibition

Barabutis

Dimitropoulou

Gregory

et al. 2018

J Cellular Molecular Medi

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“…Several regulatory factors involved in the type I interferon (IFN) pathway, such as Toll-like receptor 3 (TLR3) [5], IFN regulatory factor 9 (IRF9) and IRF5 [6,7], doublestranded RNA-dependent protein kinase R (PKR), interferon stimulated gene 15 (ISG15), and guanylate-binding protein 1 [8][9][10], are in fact the direct transcriptional targets of p53, and thereby may contribute to p53 mediated antiviral role. We previously demonstrated that p53 functioned as an essential antiviral molecule against JEV replication in vitro and in vivo [11]; however, the mechanism responsible for the p53-mediated anti-JEV response remains unknown.…”

Section: Introductionmentioning

confidence: 99%

p53 promotes ZDHHC1-mediated IFITM3 palmitoylation to inhibit Japanese encephalitis virus replication

Wang

et al. 2020

PLoS Pathog

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The tumor suppressor p53 as an innate antiviral regulator contributes to restricting Japanese encephalitis virus (JEV) replication, but the mechanism is still unclear. The interferon-induced transmembrane protein 3 (IFITM3) is an intrinsic barrier to a range of virus infection, whether IFITM3 is responsible for the p53-mediated anti-JEV response remains elusive. Here, we found that IFITM3 significantly inhibited JEV replication in a protein-palmitoylation-dependent manner and incorporated into JEV virions to diminish the infectivity of progeny viruses. Palmitoylation was also indispensible for keeping IFITM3 from lysosomal degradation to maintain its protein stability. p53 up-regulated IFITM3 expression at the protein level via enhancing IFITM3 palmitoylation. Screening of palmitoyltransferases revealed that zinc finger DHHC domain-containing protein 1 (ZDHHC1) was transcriptionally up-regulated by p53, and consequently ZDHHC1 interacted with IFITM3 to promote its palmitoylation and stability. Knockdown of IFITM3 significantly impaired the inhibitory role of ZDHHC1 on JEV replication. Meanwhile, knockdown of either ZDHHC1 or IFITM3 expression also compromised the p53-mediated anti-JEV effect. Interestingly, JEV reduced p53 expression to impair ZDHHC1 mediated IFITM3 palmitoylation for viral evasion. Our data suggest the existence of a previously unrecognized p53-ZDHHC1-IFITM3 regulatory pathway with an essential role in restricting JEV infection and provide a novel insight into JEV-host interaction.

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“…There, the virus may also influence transcription regulation of host cell genes that help to inactivate cellular anti-viral mechanisms. JEV may also prevent cell death and manipulate the cell cycle to keep the cell alive and in an optimal metabolic state, as long as viral reproduction is required [61,151,152,153,154,155,156,157,158,159]. JEV interferes with microRNAs to control the host cell [59].…”

Section: Cellular Events and Cell-to-cell Transmission Of Jevmentioning

confidence: 99%

Review of Emerging Japanese Encephalitis Virus: New Aspects and Concepts about Entry into the Brain and Inter-Cellular Spreading

Filgueira

Lannes

2019

Pathogens

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Japanese encephalitis virus (JEV) is an emerging flavivirus of the Asia-Pacific region. More than two billion people live in endemic or epidemic areas and are at risk of infection. Recently, the first autochthonous human case was recorded in Africa, and infected birds have been found in Europe. JEV may spread even further to other continents. The first section of this review covers established and new information about the epidemiology of JEV. The subsequent sections focus on the impact of JEV on humans, including the natural course and immunity. Furthermore, new concepts are discussed about JEV’s entry into the brain. Finally, interactions of JEV and host cells are covered, as well as how JEV may spread in the body through latently infected immune cells and cell-to-cell transmission of virions or via other infectious material, including JEV genomic RNA.

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Tumor suppressor p53 functions as an essential antiviral molecule against Japanese encephalitis virus

Cited by 8 publications

References 19 publications

Wild‐type p53 enhances endothelial barrier function by mediating RAC1 signalling and RhoA inhibition

Wild‐type p53 enhances endothelial barrier function by mediating RAC1 signalling and RhoA inhibition

p53 promotes ZDHHC1-mediated IFITM3 palmitoylation to inhibit Japanese encephalitis virus replication

Review of Emerging Japanese Encephalitis Virus: New Aspects and Concepts about Entry into the Brain and Inter-Cellular Spreading

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