Hepatitis B virus affects TLR2 signalling and Hippo pathway activity, thereby counter-regulates innate immunity and contributes to hepatocarcinogenesis

In summary, we demonstrate that the Hepatitis B virus (HBV) was able to stimulate TLR2, which not only mediated NF-κB signalling but also activated the Hippo pathway, which regulated the innate immune response by producing and controlling inflammatory factors. YAP/TEAD4 functioned as a key regulator and was likely important for balancing the innate immune response through the induction of IκBα. In contrast to previous reports indicating that HBV acts as a "stealth virus”, our study showed that a rapid, innate immune response occurred at a very early stage, immediately after HBV exposure, which was subsequently suppressed by IκBα and further unknown mechanisms, which may explain the ability of HBV to evade innate immunity. This rapid, innate immune response is necessary for the host defence but can also induce tissue injury when the activation is too strong. The activation of the Hippo signalling effector YAP accompanied the TLR2-NF-κB-mediated immune response and negatively regulates the activation of NF-κB to reduce tissue injury. Taken together, our data indicated that the Hippo signalling pathway acts as a regulator of the rapid, innate immune response. These findings directly link hepatic inflammation with growth control mechanisms and might explain tumour progression in non-cirrhotic, HBV-infected patients.

In HBsAg-transgenic mice, the overproduction of HBsAg caused the nuclear accumulation of YAP and BMI1, while simultaneously decreasing the expression of MST1/2 and MOB1, which are key components of the Hippo signalling pathway. In addition, the YAP/TEAD4 transcription factor complex promoted BMI1 expression, through directly binding to the promoter region of Bmi1. As an inhibitor of p16INK4a and p19ARF, BMI1 upregulation induces DNA replication and cell proliferation. DNA damage and unpaired chromatids were observed in transgenic mouse hepatocytes. These characteristic features promote chromosomal instability, leading to the development of hepatocellular carcinoma. HBsAg can be expressed as three different-sized surface polypeptides, and our findings suggested that the small HBsAg may interact with LATS1/2, forming a complex that additionally promotes the dephosphorylation and subsequent nuclear translocation of YAP. The Hippo signalling pathway plays a vital role during cell homeostasis. Our findings suggested that the HBsAg-mediated Hippo pathway inactivation results in BMI1 accumulation, possibly promoting hepatocarcinogenesis by altering the cell cycle and decreasing chromosomal stability.


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