The Role of Unfolded Protein Response in Coronavirus Infection and Its Implications for Drug Design

Xue, Mei; Feng, Li

doi:10.3389/fmicb.2021.808593

Cited by 27 publications

(20 citation statements)

References 57 publications

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“…Activation of the UPR is accompanied with changes of ER proteostasis, ER morphology and cargo proteins export, which suggest that ORF8 reshapes the ER to accommodate the requirement for virus replication and maturation. Indeed, accumulating evidences have shown that induction of the UPR may constitute a major aspect of coronavirus-host interaction [ 34 , 35 ]. Interestingly, EM images show that ORF8 promotes the ER membrane remodeling, which probably provide the major membrane source for virion assembly [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases

et al. 2022

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases

et al. 2022

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“…It has been linked to the development of a wide spectrum of pathologies, including alcoholic- and non-alcoholic liver disease, various autoimmune and inflammatory disorders, and neurodegenerative diseases [ 59 ]. Several viruses have been shown to induce UPR, including SARS-CoV-2, HCV, and HBV [ 42 , 60 ]. The above-cited paper of Williams et al states that HDV antigens do not induce UPR, despite their data on the increased expression of a reporter under the control of an ERSE element that is one of the three key elements of UPR pathways [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response

et al. 2023

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Hepatitis delta virus (HDV) is a viroid-like satellite that may co-infect individuals together with hepatitis B virus (HBV), as well as cause superinfection by infecting patients with chronic hepatitis B (CHB). Being a defective virus, HDV requires HBV structural proteins for virion production. Although the virus encodes just two forms of its single antigen, it enhances the progression of liver disease to cirrhosis in CHB patients and increases the incidence of hepatocellular carcinoma. HDV pathogenesis so far has been attributed to virus-induced humoral and cellular immune responses, while other factors have been neglected. Here, we evaluated the impact of the virus on the redox status of hepatocytes, as oxidative stress is believed to contribute to the pathogenesis of various viruses, including HBV and hepatitis C virus (HCV). We show that the overexpression of large HDV antigen (L-HDAg) or autonomous replication of the viral genome in cells leads to increased production of reactive oxygen species (ROS). It also leads to the upregulated expression of NADPH oxidases 1 and 4, cytochrome P450 2E1, and ER oxidoreductin 1α, which have previously been shown to mediate oxidative stress induced by HCV. Both HDV antigens also activated the Nrf2/ARE pathway, which controls the expression of a spectrum of antioxidant enzymes. Finally, HDV and its large antigen also induced endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR). In conclusion, HDV may enhance oxidative and ER stress induced by HBV, thus aggravating HBV-associated pathologies, including inflammation, liver fibrosis, and the development of cirrhosis and hepatocellular carcinoma.

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“…It was demonstrated that the viral proteins S, ORF3a, ORF6, ORF7a, ORF8ab, and ORF8b of SARS-CoV are able to induce ER stress. Moreover, the use of pharmacological inhibitors of the UPR pathway regulates viral replication [ 41 ]. Upregulation of this pathway has been identified also in cells infected with SARS-CoV-2 and murine hepatitis virus (MHV), often used as a model for the Betacoronavirus genus.…”

Section: Introductionmentioning

confidence: 99%

Protein Arginylation Is Regulated during SARS-CoV-2 Infection

Macedo-da-Silva

Rosa-Fernandes

Gomes

et al. 2023

Viruses

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Background: In 2019, the world witnessed the onset of an unprecedented pandemic. By February 2022, the infection by SARS-CoV-2 has already been responsible for the death of more than 5 million people worldwide. Recently, we and other groups discovered that SARS-CoV-2 infection induces ER stress and activation of the unfolded protein response (UPR) pathway. Degradation of misfolded/unfolded proteins is an essential element of proteostasis and occurs mainly in lysosomes or proteasomes. The N-terminal arginylation of proteins is characterized as an inducer of ubiquitination and proteasomal degradation by the N-degron pathway. Results: The role of protein arginylation during SARS-CoV-2 infection was elucidated. Protein arginylation was studied in Vero CCL-81, macrophage-like THP1, and Calu-3 cells infected at different times. A reanalysis of in vivo and in vitro public omics data combined with immunoblotting was performed to measure levels of arginyl-tRNA-protein transferase (ATE1) and its substrates. Dysregulation of the N-degron pathway was specifically identified during coronavirus infections compared to other respiratory viruses. We demonstrated that during SARS-CoV-2 infection, there is an increase in ATE1 expression in Calu-3 and Vero CCL-81 cells. On the other hand, infected macrophages showed no enzyme regulation. ATE1 and protein arginylation was variant-dependent, as shown using P1 and P2 viral variants and HEK 293T cells transfection with the spike protein and receptor-binding domains (RBD). In addition, we report that ATE1 inhibitors, tannic acid and merbromine (MER) reduce viral load. This finding was confirmed in ATE1-silenced cells. Conclusions: We demonstrate that ATE1 is increased during SARS-CoV-2 infection and its inhibition has potential therapeutic value.

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The Role of Unfolded Protein Response in Coronavirus Infection and Its Implications for Drug Design

Cited by 27 publications

References 57 publications

SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases

SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases

Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response

Protein Arginylation Is Regulated during SARS-CoV-2 Infection

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