Prototype foamy virus elicits complete autophagy involving the ER stress-related UPR pathway

Yuan, Peng; Dong, Lanlan; Cheng, Qingqing; Wang, Shuang; Li, Zhi; Sun, Yan; Han, Song; Yin, Jun; Peng, Biwen; He, Xiaohua; Liu, Wanhong

doi:10.1186/s12977-017-0341-x

Cited by 14 publications

(17 citation statements)

References 47 publications

(45 reference statements)

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“…The surge in protein synthesis during viral replication frequently overloads the endoplasmic reticulum, resulting in ERS [23] that triggers the unfolded protein response (UPR) to restore protein homeostasis and decrease aggregates of misfolded peptides. However, persistent UPR due to severe ERS can lead to apoptosis [24]. Consistent with this, the 143B cells treated with ZSTK474 or VSVΔ51 showed markedly swollen endoplasmic reticulum within 24 h, which increased further in the dual treated cells ( Fig.…”

Section: The Synergistic Effect Of Zstk474 and Vsvδ51 Depends On Ers-supporting

confidence: 77%

PI3K inhibitor significantly enhances the antitumor activity of oncolytic virus in osteosarcoma

Wang¹,

Yang²,

Li³

et al. 2020

Preprint

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Background: Osteosarcoma (OS) is a highly aggressive malignancy with less than 30% 5-year survival rate among patients with metastatic or recurrent cancer. However, the treatment for osteosarcoma has not been modified in the last three decades. Oncolytic viruses have shown encouraging results in pre-clinical trials, but have failed to translate into high therapeutic efficacy in clinical trials. In this study, we will determine the therapeutic effect of combining PI3K inhibitor with an oncolytic virus against osteosarcoma. Material and Methods: Osteosarcoma cell lines and xenograft model were treated with ZSTK474 and/or VSVΔ51, the tumor suppressive ability was verified by in vitro cytotoxicity experiments and in vivo antitumor activity experiments, and the antitumor mechanism was explored through the study of apoptosis-related signaling pathways. Results: ZSTK474 sensitized the osteosarcoma cells to VSVΔ51, and augmented apoptosis via endoplasmic reticulum stress. The combination treatment also showed greater in vivo tumor inhibition compared to either ZSTK474 or VSVΔ51 alone, and significantly enhanced the tumor infiltration of immune cells. Conclusion: PI3K inhibitors combined with oncolytic virus is a promising strategy against osteosarcoma.

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Section: The Synergistic Effect Of Zstk474 and Vsvδ51 Depends On Ers-supporting

confidence: 77%

PI3K inhibitor significantly enhances the antitumor activity of oncolytic virus in osteosarcoma

Wang¹,

Yang²,

Li³

et al. 2020

Preprint

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“…PERK activation contributes to DENV and BTV replication by inducing autophagy and promoting survivability of virusinfected cells (17,31,32). However, PFV infection activates PERK pathway, thereby inducing autophagy, which in turn represses PFV replication (33). PERK pathway also inhibits influenza virus replication by reducing viral protein synthesis (28).…”

Section: Discussionmentioning

confidence: 99%

Japanese Encephalitis Virus Induces Apoptosis and Encephalitis by Activating the PERK Pathway

Wang

Xin

Wang

et al. 2019

J Virol

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Accumulated evidence demonstrates that Japanese encephalitis virus (JEV) infection triggers endoplasmic reticulum (ER) stress and neuron apoptosis. ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) has been reported to induce apoptosis under acute or prolonged ER stress. However, the precise role of PERK in JEV-induced apoptosis and encephalitis remains unknown. Here, we report that JEV infection activates the PERK-ATF4-CHOP apoptosis pathway both in vitro and in vivo. PERK activation also promotes the formation of stress granule, which in turn represses JEV-induced apoptosis. However, PERK inhibitor reduces apoptosis, indicating that JEV-activated PERK predominantly induces apoptosis via the PERK-ATF4-CHOP apoptosis pathway. Among JEV proteins that have been reported to induce ER stress, only JEV NS4B can induce PERK activation. PERK has been reported to form an active molecule by dimerization. The coimmunoprecipitation assay shows that NS4B interacts with PERK. Moreover, glycerol gradient centrifugation shows that NS4B induces PERK dimerization. Both the LIG-FHA and the LIG-WD40 domains within NS4B are required to induce PERK dimerization, suggesting that JEV NS4B pulls two PERK molecules together by simultaneously interacting with them via different motifs. PERK deactivation reduces brain cell damage and encephalitis during JEV infection. Furthermore, expression of JEV NS4B is sufficient to induce encephalitis via PERK in mice, indicating that JEV activates PERK primarily via its NS4B to cause encephalitis. Taken together, our findings provide a novel insight into JEV-caused encephalitis. IMPORTANCE Japanese encephalitis virus (JEV) infection triggers endoplasmic reticulum (ER) stress and neuron apoptosis. ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) has been reported to induce apoptosis under acute or prolonged ER stress. However, whether the PERK pathway of ER stress response plays important roles in JEV-induced apoptosis and encephalitis remains unknown. Here, we found that JEV infection activates ER stress sensor PERK in neuronal cells and mouse brains. PERK activation induces apoptosis via the PERK-ATF4-CHOP apoptosis pathway upon JEV infection. Among the JEV proteins prM, E, NS1, NS2A, NS2B, and NS4B, only NS4B activates PERK. Moreover, activated PERK participates in apoptosis and encephalitis induced by JEV and NS4B. These findings provide a novel therapeutic approach for JEV-caused encephalitis.

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“…Our earlier study showed that PFV induces complete autophagy and is associated with endoplasmic reticulum (ER) stress (13). We report here that PFV Gag recruits ESCRT to promote amphisome formation and facilitate endosomal autophagic clearance of SGs.…”

mentioning

confidence: 71%

“…Also, the PFV L-domain is critical for the recruitment of tumor susceptibility gene 101 (TSG101) and apoptosis-linked gene 2 protein (ALG-2)-interacting protein X (Alix), the key factors of the ESCRT pathway, and promotes viral budding (12). Previously, we found that PFV induces autophagy, which is a membrane-associated biological process, as is viral budding (13). However, whether PFV Gag is a key factor in PFV-induced autophagy remains unknown.…”

mentioning

confidence: 99%

The Late Domain of Prototype Foamy Virus Gag Facilitates Autophagic Clearance of Stress Granules by Promoting Amphisome Formation

Zheng

Zhu²,

Yan

et al. 2020

J Virol

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Prototype foamy virus (PFV), a complex retrovirus belonging to Spumaretrovirinae, maintains lifelong latent infection. The maintenance of lifelong latent infection by viruses relies on the repression of the type I interferon (IFN) response. However, the mechanism involving PFV latency, especially regarding the suppression of the IFN response, is poorly understood. Our previous study showed that PFV promotes autophagic flux. However, the underlying mechanism and the role of PFV-induced autophagy in latent infection have not been clarified. Here, we report that the PFV viral structural protein Gag induced amphisome formation and triggered autophagic clearance of stress granules (SGs) to attenuate type I IFN production. Moreover, the late domain (L-domain) of Gag played a central role in Alix recruitment, which promoted endosomal sorting complex required for transport I (ESCRT-I) formation and amphisome accumulation by facilitating late endosome formation. Our data suggest that PFV Gag represses the host IFN response through autophagic clearance of SGs by activating the endosome-autophagy pathway. More importantly, we found a novel mechanism by which a retrovirus inhibits the SG response to repress the type I IFN response. IMPORTANCE Maintenance of lifelong latent infection for viruses relies on repression of the type I IFN response. Autophagy plays a double-edged sword in antiviral immunity. However, the role of autophagy in the regulation of the type I IFN response and the mechanism involving virus-promoted autophagy have not been fully elucidated. SGs are an immune complex associated with the antiviral immune response and are critical for type I IFN production. Autophagic clearance of SGs is one means of degradation of SGs and is associated with regulation of immunity, but the detailed mechanism remains unclear. In this article, we demonstrate that PFV Gag recruits ESCRT-I to facilitate amphisome formation. Our data also suggest that amphisome formation is a critical event for autophagic clearance of SGs and repression of the type I IFN response. More importantly, we found a novel mechanism by which a retrovirus inhibits the SG response to repress the type I IFN response.

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Prototype foamy virus elicits complete autophagy involving the ER stress-related UPR pathway

Cited by 14 publications

References 47 publications

PI3K inhibitor significantly enhances the antitumor activity of oncolytic virus in osteosarcoma

PI3K inhibitor significantly enhances the antitumor activity of oncolytic virus in osteosarcoma

Japanese Encephalitis Virus Induces Apoptosis and Encephalitis by Activating the PERK Pathway

The Late Domain of Prototype Foamy Virus Gag Facilitates Autophagic Clearance of Stress Granules by Promoting Amphisome Formation

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