African swine fever virus MGF505-11R inhibits type I interferon production by negatively regulating the cGAS-STING-mediated signaling pathway

Zhou

et al. 2022

Viruses

African swine fever virus (ASFV) is responsible for enormous economic losses in the global swine industry. The ASFV genome encodes approximate 160 proteins, most of whose functions remain largely unknown. In this study, we examined the roles of ASFV K205R in endoplasmic reticulum (ER) stress, autophagy, and inflammation. We observed that K205R was located in both the cytosolic and membrane fractions, and formed stress granules in cells. Furthermore, K205R triggered ER stress and activated the unfolded protein response through activating the transcription factor 6, ER to nucleus signaling 1, and eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3/PERK) signaling pathways. Moreover, K205R inhibited the serine/threonine kinase 1 and the mechanistic target of the rapamycin kinase signaling pathway, thereby activating unc-51 like autophagy activating kinase 1, and hence autophagy. In addition, K205R stimulated the translocation of P65 into the nucleus and the subsequent activation of the nuclear factor kappa B (NF-κB) signaling pathway. Inhibition of ER stress with a PERK inhibitor attenuated K205R-induced autophagy and NF-κB activation. Our data demonstrated a previously uncharacterized role of ASFV K205R in ER stress, autophagy, and the NF-κB signaling pathway.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

African Swine Fever Virus K205R Induces ER Stress and Consequently Activates Autophagy and the NF-κB Signaling Pathway

Zhou

et al. 2022

Viruses

“…ASFV has been reported to inhibit signaling in the cGAS-STING pathway and downregulate IFN-β levels when porcine macrophages are infected with the ASFV Armenia/07 virulent strain ( García-Belmonte et al., 2019 ). MGF-505-7R and MGF-505-11R interact with STING, inhibit the cGAS-STING signaling pathway and subvert type I IFN production ( Li et al., 2021a ; Yang K. et al., 2021 ). DP96R of the ASFV China 2018/1 strain is reported to negatively regulate type I IFN expression and NF-κB signaling by inhibiting both TBK1 and IKKβ ( Wang et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…A528R inhibits TLR8-NF-κB signaling by targeting p65 activation and nuclear translocation ( Liu X. et al., 2021 ). F317L interacts with IκB kinase β (IKKβ) and impairs NF-κB pathway activation by disrupting NF-κB activity to evade the host immune response ( Yang J. et al., 2021 ). ASFV MGF360-14L has been selected as target gene of deletion for attenuated ASF vaccine development, yet its function is still unclear.…”

Section: Introductionmentioning

confidence: 99%

African Swine Fever Virus MGF360-14L Negatively Regulates Type I Interferon Signaling by Targeting IRF3

Front. Cell. Infect. Microbiol.

Cui

Xin

et al. 2022

African swine fever (ASF) is a devastating infectious disease caused by African swine fever virus (ASFV). The ASFV genome encodes multiple structural and non-structural proteins that contribute to evasion of host immunity. In this study, we determined that the viral non-structural protein MGF360-14L inhibits interferon-β (IFN-β) promoter activity induced by cGAS-STING signaling. MGF360-14L was also found to downregulate expression of the IRF3 protein and promote its degradation through ubiquitin-meditated proteolysis. Moreover, MGF360-14L was shown to interact with and destabilize IRF3 by facilitating E3 ligase TRIM21-mediated K63-linked ubiquitination of IRF3. Overall, our study revealed that MGF360-14L promotes degradation of IRF3 through TRIM21, thereby inhibiting type I interferon production. These findings provide new insights into the mechanisms underlying ASFV immune evasion.

Animal Research and One Health

African swine fever virus E120R inhibited cGAS‐STING‐mediated IFN‐β and NF‐κB pathways

Cui,

Wang,

Chen

et al. 2023

African swine fever (ASF) is an acute and severe contagious disease triggered by the African swine fever virus (ASFV), which severely threatens the global swine industry. At present, no safe and efficacious vaccine has been provided to prevent and control this disease. The pathogenesis and immune evasion mechanism of ASFV are still unknown, which seriously hinders the development of safe and effective ASF vaccines. Certain proteins of ASFV involved in immunosuppression helped to evade the host innate immune response. The cGAS‐STING signaling pathway is important to the innate immune system. It induces the production of type I interferons (IFNs) and other cytokines by recognizing cytoplasmic DNA, mediating antimicrobial innate immunity through type I IFN, and nuclear factor‐κB (NF‐κB) pathways. In the present study, E120R, a late‐phase expression protein and a key virulent factor of ASFV inhibited cGAS‐STING mediated promoter activities of IFN‐β and NF‐κB in HEK293T cells. The ectopic expression of E120R down‐regulated IFN‐β pathway by targeting interferon regulatory factor 3 (IRF3) and p65, inhibited the phosphorylation of STING, and further inhibited the phosphorylation of TANK‐binding kinase 1 (TBK1) and IRF3, with no significant effects on p65 phosphorylation. Additionally, E120R also inhibited the NF‐κB pathways by inhibiting the nuclear translocation of p50 and p65, which was mediated by Sendai virus (SeV). Further, the study showed that the 61–80 amino acids sites in the C‐terminal domain of E120R were crucial for these functions. In conclusion, our work preliminarily elucidated a novel mechanism of inhibiting host innate immune response by ASFV E120R, which will provide a new target for the ASFV live gene deletion vaccine development and the theoretical basis for ASFV prevention.