Abstract
The COVID-19 pandemic is caused by the 2019–nCoV/SARS-CoV-2 virus. This severe acute respiratory syndrome is currently a global health emergency and needs much effort to generate an urgent practical treatment to reduce COVID-19 complications and mortality in humans. Viral infection activates various cellular responses in infected cells, including cellular stress responses such as unfolded protein response (UPR) and autophagy, following the inhibition of mTOR. Both UPR and autophagy mechanisms are involved in cellular and tissue homeostasis, apoptosis, innate immunity modulation, and clearance of pathogens such as viral particles. However, during an evolutionary arms race, viruses gain the ability to subvert autophagy and UPR for their benefit. SARS-CoV-2 can enter host cells through binding to cell surface receptors, including angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1). ACE2 blockage increases autophagy through mTOR inhibition, leading to gastrointestinal complications during SARS-CoV-2 virus infection. NRP1 is also regulated by the mTOR pathway. An increased NRP1 can enhance the susceptibility of immune system dendritic cells (DCs) to SARS-CoV-2 and induce cytokine storm, which is related to high COVID-19 mortality. Therefore, signaling pathways such as mTOR, UPR, and autophagy may be potential therapeutic targets for COVID-19. Hence, extensive investigations are required to confirm these potentials. Since there is currently no specific treatment for COVID-19 infection, we sought to review and discuss the important roles of autophagy, UPR, and mTOR mechanisms in the regulation of cellular responses to coronavirus infection to help identify new antiviral modalities against SARS-CoV-2 virus.
Highlights
Viruses, the tiniest causes of infection, with a diameter of 20–300 nm, possess eitherRNA or DNA as their genetic material
ATF6 activation increases the folding capacity of the Endoplasmic reticulum (ER), which has been verified in the murine hepatitis virus (MHV)-A59 infection model, and the transfection of severe acute respiratory syndrome (SARS)-1 8ab protein. eIF2: eukaryotic initiation factor 2; PERK: protein kinase R (PKR)-like ER kinase; IRE1: inositol-requiring enzymes; XBP1: X-box binding protein; ATF6: activating transcription factor 6; GRP78: glucose-regulated protein 78; ATF4: activating transcription factor 4; ERdj4: ER-localized DnaJ 4; p58IPK : 58 kDa inhibitor protein kinase; S1P/S2P: Site-1 protease/Site-2 protease; IFN: interferon; GADD34: growth arrest and DNA damage inducible protein 34
Accumulating evidence shows that SARS-CoV-2 infection induces ER stress in infected cells, thereby increasing oxidative stress and triggering cellular response pathways, such as the IRE1 and PERK arms of the unfolded protein response (UPR)
Summary
The tiniest causes of infection, with a diameter of 20–300 nm, possess either. The N protein has a vital role during assembly of new virus particles It attaches to the viral RNA genome to generate the ribonucleoprotein nucleocapsid core. The genomic material of SARS-CoV-2 is a messenger RNA (mRNA), which acts as a template for protein synthesis and for genomic replication, which together lead to the formation of new virus particles [10]. CMK blocks the entry of viruses and naphthofluorescein suppresses viral RNA transcription They could be promising antiviral agents to reduce virus spread and treatment of SARS-CoV-2 infection [13]. GRP78 dissociation, caused by ER stress, triggers IRE1 oligomerization and activates its cytosolic domains, leading to atypical splicing of X-box binding protein (XBP-1) mRNA as a transcription factor [24]. We provide evidence linking UPR and autophagy to coronaviruses and discuss whether such links may provide actionable targets for therapeutic interventions
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