Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses

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.

SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3

“…These data suggest that SARS-CoV-2 Spike likely inhibits RIG-I activation of IFN-I at the level of the IRF3 transcription factor. In addition to eliciting an IFN-I antiviral response, virus infections can further cause replication stress resulting in the aggregation of unfolded and misfolded proteins in the endoplasmic reticulum (ER) and the triggering of the highly conserved unfolded protein response (UPR) pathway that governs cellular homeostasis ( Movaqar et al., 2021 ; Siri et al., 2021 ). While SARS-CoV-2 Spike blocked the IFN-I response, it instead potentiated the UPR as demonstrated via increased activation of the unfold protein response element as shown via luciferase reporter assays ( Figure 3G ).…”

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

“…Additionally, some of the purple module hub-high traffic genes, such as MAPK1 ( 189 , 374 ), CUL2 ( 210 ), CMTM6 ( 162 ), TXNRD1 ( 375 ), RAB1A ( 376 ), DICER1 ( 377 ), RAB5A ( 209 ), HSP90B1 ( 343 ), MAGT1 ( 378 ), ADAM10 ( 379 , 380 ), SNX2 ( 89 ), OLA1 ( 381 ), SPTLC1 ( 382 ), SH3GLB1 ( 383 ), TIMM10B ( 384 ), and CREB1 ( 385 ) hub-high traffic TF, which are central for information exchange in this module, are potential targets for development of COVID-19 therapeutic strategies. Among these, the mitogen-activated protein kinase 1 ( MAPK1 ) hub-high traffic gene is a potential core target for many anti-COVID-19 therapeutic strategies ( 189 , 374 , 386 – 390 ).…”

Metformin Use Is Associated with Decreased Mortality in COVID-19 Patients with Diabetes: Evidence from Retrospective Studies and Biological Mechanism

“…In addition, metformin help to reduce the release of inflammatory markers by affecting the MTOR and NF-kappa B pathways [39]. Previous studies have demonstrated that SARS-CoV-2 activates several cellular responses, including cellular stress responses such as unfolded protein response (UPR) and autophagy, through the inhibition of mTOR [40]. The biological mechanism of UPR and autophagy are involved in cellular and tissue homeostasis, apoptosis, and innate immunity modulation.…”