Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins

Abstract

The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.

ORF3a Protein of Severe Acute Respiratory Syndrome Coronavirus 2 Inhibits Interferon-Activated Janus Kinase/Signal Transducer and Activator of Transcription Signaling via Elevating Suppressor of Cytokine Signaling 1

“…ORF3a, a key accessory protein of SARS-CoV-2, is implicated in virulence, infectivity, ion channel formation, and virus release ( Issa et al, 2020 ). It has been reported that ORF3a is involved in autophagy inhibition ( Miao et al, 2021 ; Zhang et al, 2021 ), inflammasome activation ( Xu et al, 2020 ), nuclear factor-κB signaling suppression ( Rui et al, 2021 ), and apoptosis ( Ren et al, 2020 ). ORF3a possesses an N-terminal, a transmembrane (TM), and a C-terminal domain.…”

Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection

“… 9 – 11 Intriguingly, SARS-CoV-2 proteins such as ORF9b, ORF3a, and 3CL, were reported to inhibit the cGAS-STING pathway. 12 , 13 These viral antagonistic mechanisms may account for the dampened type-I IFN (IFN-I) levels in some severe COVID-19 cases. 14 Despite these inhibitory machineries exploited by the virus, overt IFN activation and inflammatory responses were still detected in SARS-CoV-2-infected animals 15 , 16 and peripheral blood or respiratory tract samples from COVID-19 patients.…”

Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2

“…3CL protein inhibit K63-ubiquitin-mediated modification of STING and also decreases the function of NF-kB. Interestingly in the study that reported this results, both Orf3a and 3CL did not interfered with IRF3 activity [ 109 ].…”

“…Regarding cGAS, SARS-CoV-2 proteins Orf3a and 3CL are able to interact and inhibit cGAS-STING activity. Orf3a bind to STING independently of it C or N terminal regions, and inhibit NF-kB activity and downstream gene expression [ 109 ]. 3CL protein inhibit K63-ubiquitin-mediated modification of STING and also decreases the function of NF-kB.…”