Sequential ER stress and inflammatory responses are induced by SARS-CoV-2 ORF3 through ERphagy

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have resulted in a number of severe cases of COVID-19 and deaths worldwide. However, knowledge of SARS-CoV-2 infection, diseases and therapy remains limited, underlining the urgency of fundamental studies and drug development. Studies have shown that induction of autophagy and hijacking of autophagic machinery are essential for infection and replication of SARS-CoV-2; however, the mechanism of this manipulation and function of autophagy during SARS-CoV-2 infection remain unclear. In the present study, we identified ORF3 as an inducer of autophagy and revealed that ORF3 localizes to the ER and induces FAM134B-related ERphagy through the HMGB1-Beclin1 pathway. As a consequence, ORF3 induces ER stress and inflammatory responses through ERphagy and sensitizes cells to ER stress-induced cell death, suggesting that SARS-CoV-2 ORF3 hijacks ERphagy and then harms ER homeostasis to induce inflammatory responses through excessive ER stress. These findings reveal a sequential induction of ERphagy, ER stress and acute inflammatory responses during SARS-CoV-2 infection and provide therapeutic potential for ERphagy and ER stress-related drugs for COVID-19 treatment and prevention.ImportanceSARS-CoV-2 infection and replication require autophagosome-like double-membrane vacuoles. Inhibition of autophagy suppresses viral replication, indicating the essential role of autophagy in SARS-CoV-2 infection. However, how SARS-CoV-2 hijacks autophagy and the function of autophagy in the disease progression remain unknown. Here, we reveal that SARS-CoV-2 ORF3 induces ERphagy and consequently induces ER stress to trigger acute inflammatory responses and enhance sensitivity to ER stress-induced apoptosis. Our studies uncover ERphagy-induced inflammatory responses during SARS-CoV-2 infection and provide a promising therapeutic approach for treating SARS-CoV-2 infection and inflammatory responses in COVID-19 by manipulating autophagy and ER stress.

Executable Network of SARS-CoV-2-Host Interaction Predicts Drug Combination Treatments

“…We have explanations for five of the seven cases that diverge. Zhang, X. et al 41 shows that IFN-I is induced by expression of p3a, which the model cannot recapitulate, most likely as in our model NF-kB does not induce IFNs. Similarly, Thorne L. G. et al 43 found that inhibition of NF-kB with the IKK inhibitor TPCA-1 reduced IFN expression, a finding that is also not recapitulated by the model.…”

“…We have explanations for five of the seven cases that diverge. Zhang, X. et al 41 shows that IFN-I is induced by expression of p3a, which the model cannot recapitulate, most likely as in our model NF-kB does not induce IFNs.…”

“…In addition, several host translation inhibitors drawn from anticancer therapies were also shown to be effective by our model, including Homoharringtonine or Rapamycin (Figure 4A). Homoharringtonine has previously been identified in a profile of potential drugs targeting SARS-CoV-2 39 , believed to act through inhibition of the eukaryotic small ribosomal subunit (40S) 40 , suppressing viral replication as the virus depends on host translation machinery for production of viral proteins 41 . Homoharringtonine has cleared Phase II trials for chronic myeloid leukaemia 40 and so is a good candidate to be fast tracked for use.…”

“…Endoplasmic Reticulum (ER) stress: ER stress is caused both by imbalance of the Ang1-7:AngII ratio and also by the S and p3a proteins 35,40,41 . ER stress leads to activation of the Unfolded Protein Response (UPR) 28 .…”

COVID-19 Mortality is Associated with Impaired Innate Immunity in Pre-existing Health Conditions

“…During viral infection, ER is hijacked for entry to host cells and replication and assembly of viral genomes [30]. Emerging evidence suggests that coronavirus infection, including SARS and COVID-19, triggers ER stress that sequentially activates unfolded protein response and inflammatory reactions [31][32][33]. Indeed, besides the SEC62 and SGTB genes that degrade unfolded proteins in ER, the list of molecular risk factors contains four additional genes (UBE2J2, COPS5, MBTPS2, and PPIA) that respond to unfolded proteins.…”