Hepatitis B Surface Antigen Suppresses Host Innate Immune Responses Via Interaction With The TAK1-TAB2 Complex

Chronic hepatitis B is a major health problem worldwide,with more than 250 million chronic carriers.HBV behaves like a “stealth” virus that establishes persistent infection in hepatocytes and is hard to eliminate,on account of its strong ability to escape from the host innate immune system via almost all of its constituent proteins.The expression levels of many innate immune-related genes remain low while HBV infection continues.Regulation of HBV immune escape might be the key to eliminate it.This study aimed to determine the specific mechanism in HBsAg assisting HBV to escape from immune responses.We found that HBsAg downregulated the innate immune responses in hepatocytes.Further study revealed that HBsAg interacted with TAK1 and TAB2 specifically,inhibited the K63-linked polyubiquitination of TAB2 and the phosphorylation and polyubiquitination of TAK1,reduced the phosphorylation of downstream proteins IKB?,and blocked the nuclear translocation of NF-?B proteins(p50and p65).On the other hand,we found that the gradient expression of HBsAg downregulated the protein level of TAK1/TAB2,which is related to the autophagy pathway.Autophagy is a major catabolic process participating in many cellular processes,including the life cycle of HBV.We found that HBsAg promoted the colocalization of TAK1 and LC3,which was increased upon CQ treatment.HBsAg promoted the autophagic degradation of TAK1 and TAB2 via the formation of complexes with TAK1 and TAB2,resulting in suppression of the NF-?B pathway.Further,we verified our results in clinical samples and HBV infected HepG2-h NTCP cells.HBsAg interacted with TAK1/TAB2 in clinical samples and HBV infected HepG2-h NTCP cells.The expression of TAK1,TAB2,and the translocation of NF-?B inversely correlated with HBsAg levels in clinical liver tissues.TAK1 was colocalized with LC3 in liver tissues from HBVinfected patients.Taken together,our findings suggest a novel mechanism by which HBsAg interacts with TAK1-TAB2 complex and suppresses the activation of NF-?B signaling pathway via reduction of the post-translational modifications of TAK1-TAB2 and acceleration of their autophagic degradation.