Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has caused a global coronavirus disease 2019 (COVID‐19) pandemic that has affected the lives of billions of individuals. However, the host‐virus interactions still need further investigation to reveal the underling mechanism of SARS‐CoV‐2 pathogenesis. Here, transcriptomics analysis of SARS‐CoV‐2 infection highlighted possible correlation between host‐associated signaling pathway and virus. In detail, cAMP‐protein kinase (PKA) pathway has an essential role in SARS‐CoV‐2 infection, followed by the interaction between cyclic AMP response element binding protein (CREB) and CREB‐binding protein (CBP) could be induced and leading to the enhancement of CREB/CBP transcriptional activity. The replication of Delta and Omicron BA.5 were inhibited by about 49.4% and 44.7% after knockdown of CREB and CBP with small interfering RNAs, respectively. Furthermore, a small organic molecule naphthol AS‐E (nAS‐E), which targets on the interaction between CREB and CBP, potently inhibited SARS‐CoV‐2 wild‐type (WT) infection with comparable the half‐maximal effective concentration (EC50) 1.04 μM to Remdesivir 0.57 μM. Compared with WT virus, EC50 in Calu‐3 cells against Delta, Omicron BA.2, and Omicron BA.5 were, on average, 1.5‐fold, 1.1‐fold, and 1.5‐fold higher, respectively, nAS‐E had a satisfied antiviral effect against Omicron variants. Taken together, our study demonstrated the importance of CREB/CBP induced by cAMP‐PKA pathway during SARS‐CoV‐2 infection, and further provided a novel CREB/CBP interaction therapeutic drug targets for COVID‐19.
Tick-borne encephalitis virus (TBEV) is the causative agent of a potentially fatal neurological infection in humans. Investigating virus-host interaction is important for understanding the pathogenesis of TBEV and developing effective antiviral drugs against this virus. Here, we report that mammalian ste20-like kinase 3 (MST3) is involved in the regulation of TBEV infection. The knockdown or knockout of MST3, but not other mammalian ste20-like kinase family members, inhibited TBEV replication. The knockdown of MST3 also significantly reduced TBEV replication in mouse primary astrocytes. Life cycle analysis indicated that MST3 remarkably impaired virion assembly efficiency and specific infectivity by respectively 59% and 95% in MST3-knockout cells. We further found that MST3 interacts with the viral proteins NS2A and prM; and MST3 enhances the interaction of NS2A-NS4A. Thus, MST3-NS2A complex plays a major role in recruiting prM-E heterodimers and NS4A and mediates the virion assembly. Additionally, we found that MST3 was biotinylated and combined with other proteins (e.g., ATG5, Sec24A, and SNX4) that are associated with the cellular membrane required for TBEV infection. Overall, our study revealed a novel function for MST3 in TBEV infection and identified as a novel host factor supporting TBEV assembly.
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