Hepatitis B Surface Antigen Suppresses the Activation of Nuclear Factor Kappa B Pathway via Interaction With the TAK1-TAB2 Complex

Abstract

Chronic hepatitis B is a major health problem worldwide, with more than 250 million chronic carriers. Hepatitis B virus interferes with the host innate immune system so as to evade elimination via almost all of its constituent proteins; nevertheless, the function of HBsAg with respect to immune escape remains unclear. This study aimed to determine the role HBsAg plays in assisting HBV to escape from immune responses. We found that HBsAg suppressed the activation of the nuclear factor kappa B (NF-кB) pathway, leading to downregulation of innate immune responses. HBsAg interacted with TAK1 and TAB2 specifically, inhibiting the phosphorylation and polyubiquitination of TAK1 and the K63-linked polyubiquitination of TAB2. Autophagy is a major catabolic process participating in many cellular processes, including the life cycle of HBV. We found that HBsAg promoted the autophagic degradation of TAK1 and TAB2 via the formation of complexes with TAK1 and TAB2, resulting in suppression of the NF-κB pathway. The expression of TAK1, TAB2, and the translocation of NF-κB inversely correlated with HBsAg levels in clinical liver tissues. Taken together, our findings suggest a novel mechanism by which HBsAg interacts with TAK1-TAB2 complex and suppresses the activation of NF-κB signaling pathway via reduction of the post-translational modifications and autophagic degradation.

Molecular Characterization and Expression Analysis of TAK1, TAB1 and TAB2 of Golden Pompano (Trachinotus ovatus)

“…Besides, a TAB2-deficient mouse resulted in embryonic lethality due to liver degeneration and apoptosis [58]. These results indicate that TAB2 plays a crucial role in the liver [59], and fish TAB2 might play a similar role in the function of the liver [60].…”

Innate Immunity, Inflammation, and Intervention in HBV Infection

“…In the human myeloma B-cell line RPMI 8226, HBsAg dysregulated TLR9 malfunction by inhibiting transcription factor CREB activation [ 89 ]. Deng et al also found that HBsAg interfered the NF-κB signaling by binding to the TAK1 and TAB2 complex, leading to an attenuated immunological response [ 90 ]. In addition, a reduction of activated NK cells was found in the liver of HBsAg-expressing mice, indicating that HBV could affect immune cell activation by regulating immunosuppressive signal pathways and cytokines [ 91 ].…”

Toll-like receptor-mediated innate immunity orchestrates adaptive immune responses in HBV infection

“…Indeed, HBV components have been reported to interrupt the intracellular signaling pathways of TLRs. HBsAg inhibits IRF7 expression and nuclear translocation in pDCs (34) and also interferes with the NF-kB pathway by interacting with the TAK1-TAB2 complex (35). Moreover, HBeAg has been reported to disrupt homotypic TIR : TIR interactions and thus suppress TIR-mediated activation of the NF-kB and IFN-a promoters (36).…”