SARS-CoV-2 Nsp15 suppresses type I interferon production by inhibiting IRF3 phosphorylation and nuclear translocation

Zhang, Dianqi; Ji, Likai; Chen, Xu; He, Yumin; Sun, Yijie; Ji, Li; Zhang, Tiancheng; Shen, Quan; Wang, Xiaochun; Wang, Yan; Yang, Shixing; Zhang, Wen; Zhou, Chenglin

doi:10.1016/j.isci.2023.107705

Cited by 7 publications

(2 citation statements)

References 53 publications

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“…ORF9b antagonizes type I and III IFN by targeting multiple signaling pathways, including RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS–STING [ 126 ]. NSP15 suppresses type I IFN production by inhibiting phosphorylation and the nuclear translocation of IRF3 [ 127 ]. NSP13 inhibits type I IFN production by degrading TBK1 via p62-dependent selective autophagy [ 128 ].…”

Section: Innate Immunity To Sars-cov-2 Infection In the Airwaymentioning

confidence: 99%

Mucosal Immunity against SARS-CoV-2 in the Respiratory Tract

Noh,

Rha

2024

Pathogens

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The respiratory tract, the first-line defense, is constantly exposed to inhaled allergens, pollutants, and pathogens such as respiratory viruses. Emerging evidence has demonstrated that the coordination of innate and adaptive immune responses in the respiratory tract plays a crucial role in the protection against invading respiratory pathogens. Therefore, a better understanding of mucosal immunity in the airways is critical for the development of novel therapeutics and next-generation vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses. Since the coronavirus disease 2019 pandemic, our knowledge of mucosal immune responses in the airways has expanded. In this review, we describe the latest knowledge regarding the key components of the mucosal immune system in the respiratory tract. In addition, we summarize the host immune responses in the upper and lower airways following SARS-CoV-2 infection and vaccination, and discuss the impact of allergic airway inflammation on mucosal immune responses against SARS-CoV-2.

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Section: Innate Immunity To Sars-cov-2 Infection In the Airwaymentioning

confidence: 99%

Mucosal Immunity against SARS-CoV-2 in the Respiratory Tract

Noh,

Rha

2024

Pathogens

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“…Published reports on SARS-CoV-2 nsp15 have utilized either in vitro biochemical assays, ectopic overexpression, or bioinformatic approaches to characterize the structural and RNAbinding/cleavage capacity of SARS-CoV-2 nsp15 [25][26][27][28][29][30][31][32][33][34]. However, these studies were carried out in the absence of other viral proteins and moreover did not address the role of nsp15 in SARS-CoV-2 infection.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 nsp15 endoribonuclease antagonizes dsRNA-induced antiviral signaling

Otter,

Bracci,

Parenti

et al. 2023

Preprint

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Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has caused millions of deaths since emerging in 2019. Innate immune antagonism by lethal CoVs such as SARS-CoV-2 is crucial for optimal replication and pathogenesis. The conserved nonstructural protein 15 (nsp15) endoribonuclease (EndoU) limits activation of double-stranded (ds)RNA-induced pathways, including interferon (IFN) signaling, protein kinase R (PKR), and oligoadenylate synthetase/ribonuclease L (OAS/RNase L) during diverse CoV infections including murine coronavirus and Middle East respiratory syndrome (MERS)-CoV. To determine how nsp15 functions during SARS-CoV-2 infection, we constructed a mutant recombinant SARS-CoV-2 (nsp15mut) expressing a catalytically inactive nsp15. Infection with SARS-CoV-2 nsp15mutled to increased activation of the IFN signaling and PKR pathways in lung-derived epithelial cell lines and primary nasal epithelial air-liquid interface (ALI) cultures as well as significant attenuation of replication in ALI cultures compared to wild-type (WT) virus. This replication defect was rescued when IFN signaling was inhibited with the Janus activated kinase (JAK) inhibitor ruxolitinib. Finally, to assess nsp15 function in the context of minimal (MERS-CoV) or moderate (SARS-CoV-2) innate immune induction, we compared infections with SARS-CoV-2 nsp15mutand previously described MERS-CoV nsp15 mutants. Inactivation of nsp15 had a more dramatic impact on MERS-CoV replication than SARS-CoV-2 in both Calu3 cells and nasal ALI cultures suggesting that SARS-CoV-2 can better tolerate innate immune responses. Taken together, SARS-CoV-2 nsp15 is a potent inhibitor of dsRNA-induced innate immune response and its antagonism of IFN signaling is necessary for optimal viral replication in primary nasal ALI culture.SIGNIFICANCESevere acute respiratory syndrome coronavirus (SARS-CoV)-2 causes a spectrum of respiratory disease ranging from asymptomatic infections to severe pneumonia and death. Innate immune responses during SARS-CoV-2 infection have been associated with clinical disease severity, with robust early interferon responses in the nasal epithelium reported to be protective. Thus, elucidating mechanisms through which SARS-CoV-2 induces and antagonizes host innate immune responses is crucial to understanding viral pathogenesis. CoVs encode various innate immune antagonists, including the conserved nonstructural protein 15 (nsp15) which contains an endoribonuclease (EndoU) domain. We demonstrate that SARS-CoV-2 EndoU is a crucial interferon antagonist, by providing further evidence for the role of the conserved CoV nsp15 in antagonizing innate immune activation, thereby optimizing CoV replication.

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Characterization of ACTN4 as a novel antiviral target against SARS-CoV-2

Zhu,

Huang,

Sun

et al. 2024

Sig Transduct Target Ther

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The various mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pose a substantial challenge in mitigating the viral infectivity. The identification of novel host factors influencing SARS-CoV-2 replication holds potential for discovering new targets for broad-spectrum antiviral drugs that can combat future viral mutations. In this study, potential host factors regulated by SARS-CoV-2 infection were screened through different high-throughput sequencing techniques and further identified in cells. Subsequent analysis and experiments showed that the reduction of m6A modification level on ACTN4 (Alpha-actinin-4) mRNA leads to a decrease in mRNA stability and translation efficiency, ultimately inhibiting ACTN4 expression. In addition, ACTN4 was demonstrated to target nsp12 for binding and characterized as a competitor for SARS-CoV-2 RNA and the RNA-dependent RNA polymerase complex, thereby impeding viral replication. Furthermore, two ACTN4 agonists, YS-49 and demethyl-coclaurine, were found to dose-dependently inhibit SARS-CoV-2 infection in both Huh7 cells and K18-hACE2 transgenic mice. Collectively, this study unveils the pivotal role of ACTN4 in SARS-CoV-2 infection, offering novel insights into the intricate interplay between the virus and host cells, and reveals two potential candidates for future anti-SARS-CoV-2 drug development.

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SARS-CoV-2 Nsp15 suppresses type I interferon production by inhibiting IRF3 phosphorylation and nuclear translocation

Cited by 7 publications

References 53 publications

Mucosal Immunity against SARS-CoV-2 in the Respiratory Tract

Mucosal Immunity against SARS-CoV-2 in the Respiratory Tract

SARS-CoV-2 nsp15 endoribonuclease antagonizes dsRNA-induced antiviral signaling

Characterization of ACTN4 as a novel antiviral target against SARS-CoV-2

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