Hepatitis B virus (HBV) infection is the leading cause of chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). This study reveals a distinct mechanism underlying the regulation of HBV replication. HBV activates the homeobox A10 (HoxA10) in human hepatocytes, leukocytes, peripheral blood mononuclear cells (PBMCs), HepG2-NTCP cells, leukocytes isolated from CHB patients, and HBV-associated HCC tissues. HoxA10 in turn represses HBV replication in human hepatocytes, HepG2-NTCP cells, and BABL/c mice. Interestingly, we show that during early HBV infection, p38 MAPK and STAT3 were activated to facilitate HBV replication, however, during late HBV infection, HoxA10 was induced to attenuate HBV replication. Detailed studies reveal that HoxA10 binds to p38 MAPK and recruits the SH2 containing protein tyrosine phosphatase 1 (SHP-1) to facilitate SHP-1 in catalyzing dephosphorylation of p38 MAPK/STAT3, and thereby attenuates p38 MAPK/STAT3 activation and HBV replication. Furthermore, HoxA10 binds to HBV EnhI/X promoter and competes with STAT3 in the binding of the promoter, and thereby repress HBV transcription. Taken together, HoxA10 attenuates HBV replication through repressing the p38 MAPK/STAT3 pathway by two approaches: HoxA10 interacts with p38 MAPK and recruits SHP-1 to repress HBV replication; HoxA10 binds to EnhI/X promoter and competes with STAT3 to attenuate HBV transcription. Thus, the function of HoxA10 is similar to the action of interferon (IFN) in term of inhibition of HBV infection; however, the mechanism of HoxA10-mediated repression of HBV replication is different from the mechanism underlying IFN-induced inhibition of HBV infection.
IMPORTANCE Two billion people have been infected with HBV worldwide, about 240 million of infected patients developed into chronic hepatitis B (CHB), and 650,000 die each year from liver cirrhosis (LC) or hepatocellular carcinoma (HCC). This work elucidates a mechanism underlying the control of HBV replication. HBV infection activates HoxA10, a regulator of cell differentiation and cancer progression, in human cells and patients with CHB and HCC. HoxA10 subsequently inhibits HBV replication in human tissue culture cells and mice. Additionally, HoxA10 interacts with p38MAPK to repress the activation of p38MAPK and STAT3, and recruits and facilitates SHP-1 to catalyze dephosphorylation of p38MAPK and STAT3. Moreover, HoxA10 competes with STAT3 in the binding of HBV X promoter to repress HBV transcription. Thus, this work reveals a negative regulatory mechanism underlying the control of HBV replication and would provide new insights into the development of potential agents to control of HBV infection.