tetano
Editor, Senior Moderator
J Virol
. 2024 Apr 4:e0157323.
doi: 10.1128/jvi.01573-23. Online ahead of print. Inhibition of the RLR signaling pathway by SARS-CoV-2 ORF7b is mediated by MAVS and abrogated by ORF7b-homologous interfering peptide
Xiao Xiao[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Yanan Fu[SUP] #[/SUP][SUP] 1 2 [/SUP], Wanling You[SUP] #[/SUP][SUP] 1 2 [/SUP], Congcong Huang[SUP] 1 2 3 [/SUP], Feng Zeng[SUP] 1 2 [/SUP], Xinsheng Gu[SUP] 1 [/SUP], Xiaoguang Sun[SUP] 1 2 [/SUP], Jian Li[SUP] 1 2 [/SUP], Qiwei Zhang[SUP] 4 [/SUP], Weixing Du[SUP] 1 [/SUP], Gong Cheng[SUP] 5 [/SUP], Zhixin Liu[SUP] 1 2 3 [/SUP], Long Liu[SUP] 1 2 3 [/SUP]
Affiliations
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and characterized by dysregulated immune response. Studies have shown that the SARS-CoV-2 accessory protein ORF7b induces host cell apoptosis through the tumor necrosis factor alpha (TNF-α) pathway and blocks the production of interferon beta (IFN-β). The underlying mechanism remains to be investigated. In this study, we found that ORF7b facilitated viral infection and production, and inhibited the RIG-I-like receptor (RLR) signaling pathway through selectively interacting with mitochondrial antiviral-signaling protein (MAVS). MAVS[SUB]439-466[/SUB] region and MAVS Lys461 were essential for the physical association between MAVS and ORF7b, and the inhibition of the RLR signaling pathway by ORF7b. MAVS[SUB]K461[/SUB]/K63 ubiquitination was essential for the RLR signaling regulated by the MAVS-ORF7b complex. ORF7b interfered with the recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) and the activation of the RLR signaling pathway by MAVS. Furthermore, interfering peptides targeting the ORF7b complex reversed the ORF7b-suppressed MAVS-RLR signaling pathway. The most potent interfering peptide V disrupts the formation of ORF7b tetramers, reverses the levels of the ORF7b-inhibited physical association between MAVS and TRAF6, leading to the suppression of viral growth and infection. Overall, this study provides a mechanism for the suppression of innate immunity by SARS-CoV-2 infection and the mechanism-based approach via interfering peptides to potentially prevent SARS-CoV-2 infection.IMPORTANCEThe pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and continues to be a threat to public health. It is imperative to understand the biology of SARS-CoV-2 infection and find approaches to prevent SARS-CoV-2 infection and ameliorate COVID-19. Multiple SARS-CoV-2 proteins are known to function on the innate immune response, but the underlying mechanism remains unknown. This study shows that ORF7b inhibits the RIG-I-like receptor (RLR) signaling pathway through the physical association between ORF7b and mitochondrial antiviral-signaling protein (MAVS), impairing the K63-linked MAVS polyubiquitination and its recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) to MAVS. The most potent interfering peptide V targeting the ORF7b-MAVS complex may reverse the suppression of the MAVS-mediated RLR signaling pathway by ORF7b and prevent viral infection and production. This study may provide new insights into the pathogenic mechanism of SARS-CoV-2 and a strategy to develop new drugs to prevent SARS-CoV-2 infection.
Keywords: MAVS; ORF7b; RLR signaling pathway; SARS-CoV-2; interfering peptide.
. 2024 Apr 4:e0157323.
doi: 10.1128/jvi.01573-23. Online ahead of print. Inhibition of the RLR signaling pathway by SARS-CoV-2 ORF7b is mediated by MAVS and abrogated by ORF7b-homologous interfering peptide
Xiao Xiao[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Yanan Fu[SUP] #[/SUP][SUP] 1 2 [/SUP], Wanling You[SUP] #[/SUP][SUP] 1 2 [/SUP], Congcong Huang[SUP] 1 2 3 [/SUP], Feng Zeng[SUP] 1 2 [/SUP], Xinsheng Gu[SUP] 1 [/SUP], Xiaoguang Sun[SUP] 1 2 [/SUP], Jian Li[SUP] 1 2 [/SUP], Qiwei Zhang[SUP] 4 [/SUP], Weixing Du[SUP] 1 [/SUP], Gong Cheng[SUP] 5 [/SUP], Zhixin Liu[SUP] 1 2 3 [/SUP], Long Liu[SUP] 1 2 3 [/SUP]
Affiliations
- PMID: 38572974
- DOI: 10.1128/jvi.01573-23
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and characterized by dysregulated immune response. Studies have shown that the SARS-CoV-2 accessory protein ORF7b induces host cell apoptosis through the tumor necrosis factor alpha (TNF-α) pathway and blocks the production of interferon beta (IFN-β). The underlying mechanism remains to be investigated. In this study, we found that ORF7b facilitated viral infection and production, and inhibited the RIG-I-like receptor (RLR) signaling pathway through selectively interacting with mitochondrial antiviral-signaling protein (MAVS). MAVS[SUB]439-466[/SUB] region and MAVS Lys461 were essential for the physical association between MAVS and ORF7b, and the inhibition of the RLR signaling pathway by ORF7b. MAVS[SUB]K461[/SUB]/K63 ubiquitination was essential for the RLR signaling regulated by the MAVS-ORF7b complex. ORF7b interfered with the recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) and the activation of the RLR signaling pathway by MAVS. Furthermore, interfering peptides targeting the ORF7b complex reversed the ORF7b-suppressed MAVS-RLR signaling pathway. The most potent interfering peptide V disrupts the formation of ORF7b tetramers, reverses the levels of the ORF7b-inhibited physical association between MAVS and TRAF6, leading to the suppression of viral growth and infection. Overall, this study provides a mechanism for the suppression of innate immunity by SARS-CoV-2 infection and the mechanism-based approach via interfering peptides to potentially prevent SARS-CoV-2 infection.IMPORTANCEThe pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and continues to be a threat to public health. It is imperative to understand the biology of SARS-CoV-2 infection and find approaches to prevent SARS-CoV-2 infection and ameliorate COVID-19. Multiple SARS-CoV-2 proteins are known to function on the innate immune response, but the underlying mechanism remains unknown. This study shows that ORF7b inhibits the RIG-I-like receptor (RLR) signaling pathway through the physical association between ORF7b and mitochondrial antiviral-signaling protein (MAVS), impairing the K63-linked MAVS polyubiquitination and its recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) to MAVS. The most potent interfering peptide V targeting the ORF7b-MAVS complex may reverse the suppression of the MAVS-mediated RLR signaling pathway by ORF7b and prevent viral infection and production. This study may provide new insights into the pathogenic mechanism of SARS-CoV-2 and a strategy to develop new drugs to prevent SARS-CoV-2 infection.
Keywords: MAVS; ORF7b; RLR signaling pathway; SARS-CoV-2; interfering peptide.