Enterovirus 71 mediates cell cycle arrest in S phase through non-structural protein 3D

Yu, Jinghua; Zhang, Liying; Ren, Peiyou; Zhong, Ting; Li, Zhaolong; Wang, Zengyan; Li, Jingliang; Liu, Xin; Zhao, Ke; Zhang, Wenyan; Yu, Xiao Fang

doi:10.4161/15384101.2014.980631

Cited by 48 publications

(87 citation statements)

References 49 publications

(63 reference statements)

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“…Many investigators have tried to inhibit the activity of 3D protein and thereby inhibit viral replication [30, 47, 48]. It is also involved in the regulation of cell S-phase arrest [49] and immune response [50]. However, the role of 3D in the regulation of NLRP3 inflammasome has not been reported.…”

Section: Discussionmentioning

confidence: 99%

EV71 3D Protein Binds with NLRP3 and Enhances the Assembly of Inflammasome Complex

et al. 2017

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Activation of NLRP3 inflammasome is important for effective host defense against invading pathogen. Together with apoptosis-associated speck-like protein containing CARD domain (ASC), NLRP3 induces the cleavage of caspase-1 to facilitate the maturation of interleukin-1beta (IL-1β), an important pro-inflammatory cytokine. IL-1β subsequently plays critical roles in inflammatory responses by activating immune cells and inducing many secondary pro-inflammatory cytokines. Although the role of NLRP3 inflammasome in immune response is well defined, the mechanism underlying its assembly modulated by pathogen infection remains largely unknown. Here, we identified a novel mechanism by which enterovirus 71 (EV71) facilitates the assembly of NLRP3 inflammasome. Our results show that EV71 induces production and secretion of IL-1β in macrophages and peripheral blood mononuclear cells (PBMCs) through activation of NLRP3 inflammasome. EV71 replication and protein synthesis are required for NLRP3-mediated activation of IL-1β. Interestingly, EV71 3D protein, a RNA-dependent RNA polymerase (RdRp) was found to stimulate the activation of NLRP3 inflammasome, the cleavage of pro-caspase-1, and the release of IL-1β through direct binding to NLRP3. More importantly, 3D interacts with NLRP3 to facilitate the assembly of inflammasome complex by forming a 3D-NLRP3-ASC ring-like structure, resulting in the activation of IL-1β. These findings demonstrate a new role of 3D as an important player in the activation of inflammatory response, and identify a novel mechanism underlying the modulation of inflammasome assembly and function induced by pathogen invasion.

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Section: Discussionmentioning

confidence: 99%

EV71 3D Protein Binds with NLRP3 and Enhances the Assembly of Inflammasome Complex

et al. 2017

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“…The enhancement of viral replication in an arrest state has also been reported for other RNA viruses (32,50); however, the specific mechanisms by which this enhancement occurs remain unclear. While we have demonstrated that induction of an S-phase arrest state leads to increased ZIKV protein expression, RNA levels, and titers, we have not yet explicitly determined at which stage of the viral life cycle this enhancement occurs.…”

Section: Discussionmentioning

confidence: 74%

Zika Virus Infection Induces DNA Damage Response in Human Neural Progenitors That Enhances Viral Replication

Hammack

Ogden

Madden

et al. 2019

J Virol

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Zika virus (ZIKV) infection attenuates the growth of human neural progenitor cells (hNPCs). As these hNPCs generate the cortical neurons during early brain development, the ZIKV-mediated growth retardation potentially contributes to the neurodevelopmental defects of the congenital Zika syndrome. Here, we investigate the mechanism by which ZIKV manipulates the cell cycle in hNPCs and the functional consequence of cell cycle perturbation on the replication of ZIKV and related flaviviruses. We demonstrate that ZIKV, but not dengue virus (DENV), induces DNA double-strand breaks (DSBs), triggering the DNA damage response through the ATM/Chk2 signaling pathway while suppressing the ATR/Chk1 signaling pathway. Furthermore, ZIKV infection impedes the progression of cells through S phase, thereby preventing the completion of host DNA replication. Recapitulation of the S-phase arrest state with inhibitors led to an increase in ZIKV replication, but not of West Nile virus or DENV. Our data identify ZIKV's ability to induce DSBs and suppress host DNA replication, which results in a cellular environment favorable for its replication. IMPORTANCE Clinically, Zika virus (ZIKV) infection can lead to developmental defects in the cortex of the fetal brain. How ZIKV triggers this event in developing neural cells is not well understood at a molecular level and likely requires many contributing factors. ZIKV efficiently infects human neural progenitor cells (hNPCs) and leads to growth arrest of these cells, which are critical for brain development. Here, we demonstrate that infection with ZIKV, but not dengue virus, disrupts the cell cycle of hNPCs by halting DNA replication during S phase and inducing DNA damage. We further show that ZIKV infection activates the ATM/Chk2 checkpoint but prevents the activation of another checkpoint, the ATR/Chk1 pathway. These results unravel an intriguing mechanism by which an RNA virus interrupts host DNA replication. Finally, by mimicking virus-induced S-phase arrest, we show that ZIKV manipulates the cell cycle to benefit viral replication.

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“…Influenza A virus induces favorable conditions for viral protein accumulation and virus production by inducing G 0 /G 1 cell cycle arrest in infected cells (45). Enterovirus 71 mediates cell cycle arrest in S phase through its nonstructural protein 3D (46). HIV-1 Vif protein promotes the G 1 /S transition to promote infection and latency (47).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Deregulates the Cell Cycle To Promote Viral Replication and a Premalignant Phenotype

Xia

Cheng

et al. 2018

J Virol

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Hepatitis B virus (HBV) infection is a major health problem worldwide, and chronically infected individuals are at high risk of developing cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms whereby HBV causes HCC are largely unknown. Using a biologically relevant system of HBV infection of primary human hepatocytes (PHHs), we studied how HBV perturbs gene expression and signaling pathways of infected hepatocytes and whether these effects are relevant to productive HBV infection and HBV-associated HCC. Using a human growth factor antibody array, we first showed that HBV infection induced a distinct profile of growth factor production by PHHs, marked particularly by significantly lower levels of the transforming growth factor β (TGF-β) family of proteins in the supernatant. Transcriptome profiling next revealed multiple changes in cell proliferation and cell cycle control pathways in response to HBV infection. A human cell cycle PCR array validated deregulation of more than 20 genes associated with the cell cycle in HBV-infected PHHs. Cell cycle analysis demonstrated that HBV-infected PHHs are enriched in the G/M phase compared to the predominantly G/G phase of cultured PHHs. HBV proviral host factors, such as PPARA, RXRA, and CEBPB, were upregulated upon HBV infection and particularly enriched in cells in the G/M phase. Together, these results support the notion that HBV deregulates cell cycle control to render a cellular environment that is favorable for productive HBV infection. By perturbing cell cycle regulation of infected cells, HBV may coincidently induce a premalignant phenotype that predisposes infected hepatocytes to subsequent malignant transformation. Hepatitis B virus (HBV) infection is a major health problem with high risk of developing hepatocellular carcinoma (HCC). By using a biologically relevant system of HBV infection of primary human hepatocytes (PHHs), we studied how HBV perturbs gene expression and whether these effects are relevant to HBV-associated HCC. HBV induced a distinct profile of growth factor production, marked particularly by significantly lower levels of the transforming growth factor β (TGF-β) family of proteins. Transcriptome profiling revealed multiple changes in cell proliferation and cell cycle control pathways. Cell cycle analysis demonstrated that HBV-infected PHHs are enriched in the G/M phase. HBV proviral host factors were upregulated upon infection and particularly enriched in cells in the G/M phase. Together, these results support the notion that HBV deregulates cell cycle control to render a cellular environment that is favorable for productive infection. This may coincidently induce a premalignant phenotype that predisposes infected hepatocytes to subsequent malignant transformation.

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Enterovirus 71 mediates cell cycle arrest in S phase through non-structural protein 3D

Cited by 48 publications

References 49 publications

EV71 3D Protein Binds with NLRP3 and Enhances the Assembly of Inflammasome Complex

EV71 3D Protein Binds with NLRP3 and Enhances the Assembly of Inflammasome Complex

Zika Virus Infection Induces DNA Damage Response in Human Neural Progenitors That Enhances Viral Replication

Hepatitis B Virus Deregulates the Cell Cycle To Promote Viral Replication and a Premalignant Phenotype

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