Activation of JNK1/2 and p38 MAPK signaling pathways promotes enterovirus 71 infection in immature dendritic cells

Peng, Hongjun; Shi, Mei; Zhang, Li; Li, Yuanyuan; Sun, Jing; Zhang, Lirong; Wang, Xiaohui; Xu, Xiaopeng; Zhang, Xiaolei; Mao, Yi-Jie; Ji, Yun; Jiang, Jingting; Shi, Weifeng

doi:10.1186/1471-2180-14-147

Cited by 53 publications

(45 citation statements)

References 48 publications

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“…The activation of JNK in enterovirus-infected cells has been previously described in other cell types [35, 58] but this was associated with an increase in viral amplification for enterovirus 71 only, by an unknown mechanism [41]. In β cells, CVB5 infection induces a significant increase in JNK activation that contributes to the early stages of the viral life cycle, preceding cell death.…”

Section: Discussionmentioning

confidence: 87%

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Coxsackievirus B Tailors the Unfolded Protein Response to Favour Viral Amplification in Pancreatic β Cells

et al. 2019

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Type 1 diabetes (T1D) is an autoimmune disease characterized by islet inflammation and progressive pancreatic β cell destruction. The disease is triggered by a combination of genetic and environmental factors, but the mechanisms leading to the triggering of early innate and late adaptive immunity and consequent progressive pancreatic β cell death remain unclear. The insulin-producing β cells are active secretory cells and are thus particularly sensitive to endoplasmic reticulum (ER) stress. ER stress plays an important role in the pathologic pathway leading to autoimmunity, islet inflammation, and β cell death. We show here that group B coxsackievirus (CVB) infection, a putative causative factor for T1D, induces a partial ER stress in rat and human β cells. The activation of the PERK/ATF4/CHOP branch is blunted while the IRE1α branch leads to increased spliced XBP1 expression and c-Jun N-terminal kinase (JNK) activation. Interestingly, JNK1 activation is essential for CVB amplification in both human and rat β cells. Furthermore, a chemically induced ER stress preceding viral infection increases viral replication, in a process dependent on IRE1α activation. Our findings show that CVB tailors the unfolded protein response in β cells to support their replication, preferentially triggering the pro-viral IRE1α/XBP1s/JNK1 pathway while blocking the pro-apoptotic PERK/ATF4/CHOP pathway.

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Section: Discussionmentioning

confidence: 87%

“…S5 Fig.). JNK regulates viral replication in other cell types [39-41]. To investigate whether this is the case also in β cells, we infected INS-1E cells with CVB5 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Coxsackievirus B Tailors the Unfolded Protein Response to Favour Viral Amplification in Pancreatic β Cells

et al. 2019

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“…In fact, two explanations will support our results. First, in addition to the classical heterodimer, nonclassical and variable AP-1 heterodimers have been reported as well (16,18,46,47), and this may account for the interaction and synergy between MVP and c-Fos but not ATF-2. Second, we cannot exclude the possibility that c-Jun participates in IL6 and IL8 activation as a heterodimer with c-Fos, of which physical interaction is unique to the particular family member.…”

Section: Discussionmentioning

confidence: 99%

Inducible Major Vault Protein Plays a Pivotal Role in Double-Stranded RNA– or Virus-Induced Proinflammatory Response

Peng

Shi

Xia

et al. 2016

The Journal of Immunology

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Pathogen invasion triggers robust antiviral cytokine production via different transcription factor signaling pathways. We have previously demonstrated that major vault protein (MVP) induces type I IFN production during viral infection; however, little is known about the role of MVP in proinflammatory responses. In this study, we found in vitro that expression of MVP, IL-6, and IL-8 was inducible upon dsRNA stimulation or viral infection. Moreover, MVP was essential for the induction of IL-6 and IL-8, as impaired expression of IL-6 and IL-8 in MVP-deficient human PBMCs, human lung epithelial cells (A549), and THP-1 monocytes, as well as in murine splenocytes, peritoneal macrophages, and PBMCs from MVP-knockout (MVP−/−) mice, was observed. Upon investigation of the underlying mechanisms, we demonstrated that MVP acted in synergy with AP-1 (c-Fos) and CCAAT/enhancer binding protein (C/EBP)β–liver-enriched transcriptional activating protein to activate the IL6 and IL8 promoters. Introduction of mutations into the AP-1 and C/EBPβ binding sites on the IL6 and IL8 promoters resulted in the loss of synergistic activation with MVP. Furthermore, we found that MVP interacted with both c-Fos and C/EBPβ. The interactions promoted nuclear translocation and recruitment of these transcription factors to IL6 and IL8 promoter regions. In the MVP−/− mouse model, significantly decreased expression of early antiviral cytokines resulted in higher viral titer in the lung, higher mortality, and heavier lung damage after infection with lethal influenza A virus. Taken together, our findings help to delineate a novel role of MVP in host proinflammatory response.

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“…The overexpression of XBP1 in cells appeared to inhibit viral entry, and therefore reduce viral RNA and viral particle formation (Jheng et al, 2012). As previous studies have reported that picornavirus infections induce JNK activation (Kim et al, 2004;Peng et al, 2014), further detailed studies of the IRE1-JNK activation in EV71 infection would extend our understanding of the contributions of IRE1-JNK in the virus life cycle.…”

Section: Ire1 Pathwaymentioning

confidence: 86%

ER stress, autophagy, and RNA viruses

2014

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Endoplasmic reticulum (ER) stress is a general term for representing the pathway by which various stimuli affect ER functions. ER stress induces the evolutionarily conserved signaling pathways, called the unfolded protein response (UPR), which compromises the stimulus and then determines whether the cell survives or dies. In recent years, ongoing research has suggested that these pathways may be linked to the autophagic response, which plays a key role in the cell's response to various stressors. Autophagy performs a self-digestion function, and its activation protects cells against certain pathogens. However, the link between the UPR and autophagy may be more complicated. These two systems may act dependently, or the induction of one system may interfere with the other. Experimental studies have found that different viruses modulate these mechanisms to allow them to escape the host immune response or, worse, to exploit the host's defense to their advantage; thus, this topic is a critical area in antiviral research. In this review, we summarize the current knowledge about how RNA viruses, including influenza virus, poliovirus, coxsackievirus, enterovirus 71, Japanese encephalitis virus, hepatitis C virus, and dengue virus, regulate these processes. We also discuss recent discoveries and how these will produce novel strategies for antiviral treatment.

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Activation of JNK1/2 and p38 MAPK signaling pathways promotes enterovirus 71 infection in immature dendritic cells

Cited by 53 publications

References 48 publications

Coxsackievirus B Tailors the Unfolded Protein Response to Favour Viral Amplification in Pancreatic β Cells

Coxsackievirus B Tailors the Unfolded Protein Response to Favour Viral Amplification in Pancreatic β Cells

Inducible Major Vault Protein Plays a Pivotal Role in Double-Stranded RNA– or Virus-Induced Proinflammatory Response

ER stress, autophagy, and RNA viruses

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