Seneca valley virus activates autophagy through the PERK and ATF6 UPR pathways

Hou, Lei; Dong, Jing; Zhu, Shanshan; Yan, Feng; Wei, Li; Wang, Jing; Quan, Rong; Chu, Jun; Wang, Dan; Jiang, Haijun; Xi, Yanyang; Li, Zixuan; Song, Huiqi; Guo, Yuxin; Lv, Moran; Liu, Jue

doi:10.1016/j.virol.2019.08.029

Cited by 41 publications

(23 citation statements)

References 52 publications

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“…Therefore, it is possible that in U87 cells, Simva–TMZ-induced cell death is regulated via autophagy and UPR and connected to sterol regulatory element-binding proteins. Interestingly, chemoresistance in chordoma was shown to be related to PERK–autophagy crosstalk, and it was suggested that targeting this pathway could potentially overcome chemoresistance in these cells [ 71 ]. Seneca valley virus infection-induced autophagy is connected to UPR via the PERK and ATF6 arms, which shows the connection of autophagy to UPR in different cellular stress responses [ 71 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, chemoresistance in chordoma was shown to be related to PERK–autophagy crosstalk, and it was suggested that targeting this pathway could potentially overcome chemoresistance in these cells [ 71 ]. Seneca valley virus infection-induced autophagy is connected to UPR via the PERK and ATF6 arms, which shows the connection of autophagy to UPR in different cellular stress responses [ 71 ]. ATG proteins (ATG5, ATG7, and ATG5/ATG7 together) are involved in the regulation of autophagy, ER stress, and apoptosis through PERK signaling in chondrocytes; PERK has emerged to act as a hub to connect these three vital signaling pathways [ 72 ].…”

Section: Discussionmentioning

confidence: 99%

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Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Dastghaib

Shojaei

Mostafavi‐Pour

et al. 2020

Cells

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Glioblastoma (GBM) is the most prevalent malignant primary brain tumor with a very poor survival rate. Temozolomide (TMZ) is the common chemotherapeutic agent used for GBM treatment. We recently demonstrated that simvastatin (Simva) increases TMZ-induced apoptosis via the inhibition of autophagic flux in GBM cells. Considering the role of the unfolded protein response (UPR) pathway in the regulation of autophagy, we investigated the involvement of UPR in Simva–TMZ-induced cell death by utilizing highly selective IRE1 RNase activity inhibitor MKC8866, PERK inhibitor GSK-2606414 (PERKi), and eIF2α inhibitor salubrinal. Simva–TMZ treatment decreased the viability of GBM cells and significantly increased apoptotic cell death when compared to TMZ or Simva alone. Simva–TMZ induced both UPR, as determined by an increase in GRP78, XBP splicing, eukaryote initiation factor 2α (eIF2α) phosphorylation, and inhibited autophagic flux (accumulation of LC3β-II and inhibition of p62 degradation). IRE1 RNase inhibition did not affect Simva–TMZ-induced cell death, but it significantly induced p62 degradation and increased the microtubule-associated proteins light chain 3 (LC3)β-II/LC3β-I ratio in U87 cells, while salubrinal did not affect the Simva–TMZ induced cytotoxicity of GBM cells. In contrast, protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibition significantly increased Simva–TMZ-induced cell death in U87 cells. Interestingly, whereas PERK inhibition induced p62 accumulation in both GBM cell lines, it differentially affected the LC3β-II/LC3β-I ratio in U87 (decrease) and U251 (increase) cells. Simvastatin sensitizes GBM cells to TMZ-induced cell death via a mechanism that involves autophagy and UPR pathways. More specifically, our results imply that the IRE1 and PERK signaling arms of the UPR regulate Simva–TMZ-mediated autophagy flux inhibition in U251 and U87 GBM cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Dastghaib

Shojaei

Mostafavi‐Pour

et al. 2020

Cells

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“…ER stress activates three major signaling pathways of the UPR, which are mediated through PERK kinase, IRE1, and ATF6, respectively ( Hou et al, 2019 ; Rashid et al, 2017 ). We first investigated whether the ATF6 branch of UPR is activated when orf8L or orf8S are overexpressed.…”

Section: Resultsmentioning

confidence: 99%

The ORF8 protein of SARS-CoV-2 induced endoplasmic reticulum stress and mediated immune evasion by antagonizing production of interferon beta

et al. 2021

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The open reading frame 8 (orf8) is an accessory protein of SARS-CoV-2. It has 121 amino acids with two genotypes, orf8L and orf8S. In this study, we overexpressed the orf8L and orf8S of SARS-CoV-2 as well as the orf8b of SARS-CoV to investigate their roles in the regulation of endoplasmic reticulum (ER) stress and the inhibition of interferon beta (IFNß) production. We found that the two genotypes of SARS-CoV-2 orf8 are capable of inducing ER stress without significant difference by triggering the activating transcription factor 6 (ATF6) and inositol-requiring enzymes 1 (IRE1) branches of the ER stress pathway. However, the third branch of ER stress pathway, i.e. the protein kinase-like ER kinase (PERK), was unaffected by the overexpression of SARS-CoV-2 orf8L or orf8S. Moreover, both orf8L and orf8S of SARS-CoV-2 are capable of down regulating the production of IFNß and interferon-stimulated genes (ISG), ISG15 and ISG56 induced by polyinosinic-polycytidylic acid (poly (I:C)). Moreover, we also found decreased nuclear translocation of Interferon regulatory factor 3 (IRF3), after overexpressing orf8L and orf8S induced by poly (I:C). Our data demonstrated that SARS-CoV-2 orf8 protein could induce ER stress by activating the ATF6 and IRE1 pathways, but not the PERK pathway, and functions as an interferon antagonist to inhibit the production of IFNß. However, these functions appeared not to be affected by the genotypes of SARS-CoV-2 orf8L and orf8S.

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“…PERK, as one player of the UPR, prevents protein production, hence alleviating the ER burden [143]. For certain viruses, PERK activation was reported to be beneficial, notably for NDV [144] and Seneca Valley virus [145]. Here, PERK-induced autophagy is essential for viral replication.…”

Section: Pkr-like Endoplasmic Reticulum Kinase (Eif2ak3)mentioning

confidence: 99%

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

Eiermann

Haneke

Sun

et al. 2020

Viruses

117

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Cells have evolved highly specialized sentinels that detect viral infection and elicit an antiviral response. Among these, the stress-sensing protein kinase R, which is activated by double-stranded RNA, mediates suppression of the host translation machinery as a strategy to limit viral replication. Non-translating mRNAs rapidly condensate by phase separation into cytosolic stress granules, together with numerous RNA-binding proteins and components of signal transduction pathways. Growing evidence suggests that the integrated stress response, and stress granules in particular, contribute to antiviral defense. This review summarizes the current understanding of how stress and innate immune signaling act in concert to mount an effective response against virus infection, with a particular focus on the potential role of stress granules in the coordination of antiviral signaling cascades.

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Seneca valley virus activates autophagy through the PERK and ATF6 UPR pathways

Cited by 41 publications

References 52 publications

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

The ORF8 protein of SARS-CoV-2 induced endoplasmic reticulum stress and mediated immune evasion by antagonizing production of interferon beta

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

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