Dual-specificity tyrosine-regulated kinase 4 modulates the STAT3-FOS signaling axis to inhibit hepatitis B virus replication autophagy.

Chronic hepatitis B virus (HBV) infection is a major global cause of hepatocellular carcinoma (HCC). Despite available antiviral strategies, the therapeutic eradication of HBV from infected cells remains challenging. Recent studies have highlighted the role of dual-specificity tyrosine-regulated kinases (DYRKs) in innate immunity against viruses and HCC; however, the antiviral function of DYRK4 against HBV infection remains unknown. Here, we report that DYRK4 efficiently inhibited HBV replication both and . Mechanistically, we demonstrate a direct interaction between TAB1 (TGF-beta activated kinase 1 [MAP3K7] binding protein 1) and the kinase domain of DYRK4, which may inhibit HBV replication. Importantly, we found that the kinase activity of DYRK4 plays a key role in inhibiting HBV replication its K133 site. Further, we revealed that DYRK4-induced STAT3 ubiquitination degradation results in decreased STAT3 translocation into the nucleus. Subsequently, this reduction in STAT3 downregulates FOS expression to decrease autophagy-inducible factor BECN1 (Beclin1) and LC3 I/II expression, which inhibited HBV replication autophagy. Overall, these findings identify a novel antiviral function of DYRK4 against HBV replication The ability of the DYRK4-K133 kinase activity to downregulate autophagy STAT3-FOS axis presents a potential therapeutic target for hepatitis B.