Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 May 5;46(5):4286-4308.
doi: 10.3390/cimb46050261.

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

Panagiotis Keramidas  1 , Maria Pitou  1 , Eleni Papachristou  1 , Theodora Choli-Papadopoulou  1
Affiliations
Review

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

Panagiotis Keramidas et al. Curr Issues Mol Biol. .

Abstract

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.

Keywords: ATF6; CoV; ER stress; IRE1; PERK; coronavirus; pharmacological inhibition; unfolded protein response.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The general structural and genomic characteristics of the members of coronavirus family. Adapted from “Human Coronavirus Structure” and “Genome organization of SARS-CoV” by BioRender.com. Retrieved from https://app.biorender.com/biorender-templates (accessed on 28 March 2024).
Figure 2
Figure 2
The unfolded protein response mechanism. The activation and the signal transduction of the three (ATF6, IRE1, and PERK) sensors of UPR. Each respective pathway activates the transcription of a specific pool of genes to relieve ER stress and maintain ER and cell homeostasis. However, extended activation of UPR can lead to apoptosis or other pathological conditions. Retrieved from https://app.biorender.com/biorender-templates (accessed on 28 March 2024). Adapted from “Intracellular Layout—Endoplasmic Reticulum Signaling to Nucleus” by BioRender.com (accessed on 24 April 2024).
Figure 3
Figure 3
The interference of alphacoronaviruses and their viral factors on various UPR elements. The green arrows indicate positive regulation of the respective factor. Retrieved from https://app.biorender.com/biorender-templates (accessed on 28 March 2024). Adapted from “Intracellular Layout—Endoplasmic Reticulum Signaling to Nucleus” by BioRender.com (accessed on 24 April 2024).
Figure 4
Figure 4
The perturbation of SARS-CoV-2 and its viral factors on the three pathways of UPR mechanism. The green arrows indicate positive regulation of the respective factor. Retrieved from https://app.biorender.com/biorender-templates (accessed on 28 March 2024). Adapted from “Intracellular Layout—Endoplasmic Reticulum Signaling to Nucleus” by BioRender.com (accessed on 24 April 2024).
Figure 5
Figure 5
The interference sites of IBV (gammacoronavirus) and PDCoV (deltacoronavirus) in UPR mechanism. The green arrows indicate positive regulation of the respective factor. Retrieved from https://app.biorender.com/biorender-templates (accessed on 28 March 2024). Adapted from “Intracellular Layout—Endoplasmic Reticulum Signaling to Nucleus” by BioRender.com (accessed on 24 April 2024).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Perkins H.T., Allan V. Intertwined and Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, and Diseases. Cells. 2021;10:2341. doi: 10.3390/cells10092341. - DOI - PMC - PubMed
    1. Bhattarai K.R., Riaz T.A., Kim H.-R., Chae H.-J. The Aftermath of the Interplay between the Endoplasmic Reticulum Stress Response and Redox Signaling. Exp. Mol. Med. 2021;53:151–167. doi: 10.1038/s12276-021-00560-8. - DOI - PMC - PubMed
    1. Read A., Schröder M. The Unfolded Protein Response: An Overview. Biology. 2021;10:384. doi: 10.3390/biology10050384. - DOI - PMC - PubMed
    1. Chen X., Shi C., He M., Xiong S., Xia X. Endoplasmic Reticulum Stress: Molecular Mechanism and Therapeutic Targets. Signal Transduct. Target. Ther. 2023;8:352. doi: 10.1038/s41392-023-01570-w. - DOI - PMC - PubMed
    1. Radanović T., Ernst R. The Unfolded Protein Response as a Guardian of the Secretory Pathway. Cells. 2021;10:2965. doi: 10.3390/cells10112965. - DOI - PMC - PubMed

LinkOut - more resources