Autophagy is induced by swine acute diarrhea syndrome coronavirus through the cellular IRE1-JNK-Beclin 1 signaling pathway after an interaction of viral membrane-associated papain-like protease and GRP78

Da, Shi; Zhou, Ling; Shi, Hongyan; Zhang, Jiyu; Zhang, Jialin; Zhang, Liaoyuan; Liu, Dakai; Feng, Tingshuai; Zeng, Miaomiao; Chen, Jianfei; Zhang, Xin; Xue, Mei; Jing, Zhaoyang; Li, Jianbo; Ji, Zhaoyang; He, Haojie; Guo, Longjun; Ma, Jingyun; Feng, Li

doi:10.1371/journal.ppat.1011201

Cited by 7 publications

(7 citation statements)

References 114 publications

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“…SADS-CoV is a newly discovered porcine enteric coronavirus in southern China, which can cause severe and acute diarrhea and rapid weight loss in piglets [3]. The pathogenic mechanisms of SADS-CoV infection have so far not been fully characterized [35]. As a molecular mediator of innate antiviral immunity, CH25H encodes 272 and 270 amino acids in human and porcine cells and converts cholesterol to 25HC [36].…”

Section: Discussionmentioning

confidence: 99%

Cholesterol 25-Hydroxylase Suppresses Swine Acute Diarrhea Syndrome Coronavirus Infection by Blocking Spike Protein-Mediated Membrane Fusion

Liu,

Shi,

Shi

et al. 2023

Viruses

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Swine acute diarrhea syndrome coronavirus (SADS-CoV) is an emerging porcine intestinal coronavirus that can cause acute diarrhea, vomiting, rapid weight loss, and high mortality in newborn piglets. Cholesterol 25-hydroxylase (CH25H) is a molecular mediator of innate antiviral immunity and converts cholesterol to 25-hydroxycholesterol (25HC). Previous studies have reported that CH25H and 25HC have an antiviral effect against multiple viruses. However, the interplay between SADS-CoV infection and CH25H or 25HC is still uncertain. Here, we found that CH25H and its enzymatic product 25HC restrained SADS-CoV replication by blocking membrane fusion. Our results show that CH25H was upregulated by SADS-CoV infection in vitro and in vivo, and that it was an IFN-stimulated gene in porcine ileum epithelial cells. Moreover, CH25H and CH25H mutants lacking catalytic activity can inhibit SADS-CoV replication. Furthermore, 25HC significantly suppressed SADS-CoV infection by inhibiting virus entry. Notably, we confirmed that CH25H and 25HC blocked SADS-CoV spike protein-mediated membrane fusion. Our data provide a possible antiviral therapy against SADS-CoV and other conceivable emerging coronaviruses in the future.

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Section: Discussionmentioning

confidence: 99%

Cholesterol 25-Hydroxylase Suppresses Swine Acute Diarrhea Syndrome Coronavirus Infection by Blocking Spike Protein-Mediated Membrane Fusion

Liu,

Shi,

Shi

et al. 2023

Viruses

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“…For instance, autophagy is induced by HCV (Hepatitis C virus) through PERK/ATF6 of the UPR pathway [70]. SADS-CoV (Swine acute diarrhea syndrome coronavirus) activated autophagy through IRE1α of the UPR pathway [71]. Furthermore, inhibiting UPR not only hampers autophagy but also impedes viral replication during SADS-CoV and PEDV infection [71,72].…”

Section: Discussionmentioning

confidence: 99%

Seneca Valley Virus Degrades STING via PERK and ATF6-Mediated Reticulophagy

Bai,

Zhang,

Zheng

et al. 2023

Viruses

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Seneca Valley Virus (SVV), a member of the Picornaviridae family, is an emerging porcine virus that can cause vesicular disease in pigs. However, the immune evasion mechanism of SVV remains unclear, as does its interaction with other pathways. STING (Stimulator of interferon genes) is typically recognized as a critical factor in innate immune responses to DNA virus infection, but its role during SVV infection remains poorly understood. In the present study, we observed that STING was degraded in SVV-infected PK-15 cells, and SVV replication in the cells was affected when STING was knockdown or overexpressed. The STING degradation observed was blocked when the SVV-induced autophagy was inhibited by using autophagy inhibitors (Chloroquine, Bafilomycin A1) or knockdown of autophagy related gene 5 (ATG5), suggesting that SVV-induced autophagy is responsible for STING degradation. Furthermore, the STING degradation was inhibited when reticulophagy regulator 1 (FAM134B), a reticulophagy related receptor, was knocked down, indicating that SVV infection induces STING degradation via reticulophagy. Further study showed that in eukaryotic translation initiation factor 2 alpha kinase 3 (PERK)/activating transcription factor 6 (ATF6) deficient cells, SVV infection failed to induce reticulophagy-medaited STING degradation, indicating that SVV infection caused STING degradation via PERK/ATF6-mediated reticulophagy. Notably, blocking reticulophagy effectively hindered SVV replication. Overall, our study suggested that SVV infection resulted in STING degradation via PERK and ATF6-mediated reticulophagy, which may be an immune escape strategy of SVV. This finding improves the understanding of the intricate interplay between viruses and their hosts and provides a novel strategy for the development of novel antiviral drugs.

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“…Recently, it was indicated that SADS-CoV upregulates Grp78, thus causing ER stress, and induces all three branches of the UPR both in vitro and in vivo. SADS-CoV and its papain-like protease can recruit the IRE1 pathway of the UPR to promote autophagy-induced viral replication [85] (Figure 3). However, our knowledge regarding SADS-CoV interactions with the host's cells is limited due to the short time that has passed since its first appearance.…”

Section: Swine Acute Diarrhea Syndrome (Sads-cov)mentioning

confidence: 99%

Insights into the Activation of Unfolded Protein Response Mechanism during Coronavirus Infection

Keramidas,

Pitou,

Papachristou

et al. 2024

CIMB

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Coronaviruses represent a significant class of viruses that affect both animals and humans. Their replication cycle is strongly associated with the endoplasmic reticulum (ER), which, upon virus invasion, triggers ER stress responses. The activation of the unfolded protein response (UPR) within infected cells is performed from three transmembrane receptors, IRE1, PERK, and ATF6, and results in a reduction in protein production, a boost in the ER’s ability to fold proteins properly, and the initiation of ER-associated degradation (ERAD) to remove misfolded or unfolded proteins. However, in cases of prolonged and severe ER stress, the UPR can also instigate apoptotic cell death and inflammation. Herein, we discuss the ER-triggered host responses after coronavirus infection, as well as the pharmaceutical targeting of the UPR as a potential antiviral strategy.

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Autophagy is induced by swine acute diarrhea syndrome coronavirus through the cellular IRE1-JNK-Beclin 1 signaling pathway after an interaction of viral membrane-associated papain-like protease and GRP78

Cited by 7 publications

References 114 publications

Cholesterol 25-Hydroxylase Suppresses Swine Acute Diarrhea Syndrome Coronavirus Infection by Blocking Spike Protein-Mediated Membrane Fusion

Cholesterol 25-Hydroxylase Suppresses Swine Acute Diarrhea Syndrome Coronavirus Infection by Blocking Spike Protein-Mediated Membrane Fusion

Seneca Valley Virus Degrades STING via PERK and ATF6-Mediated Reticulophagy

Insights into the Activation of Unfolded Protein Response Mechanism during Coronavirus Infection

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