Interaction between the Hepatitis B Virus and Cellular FLIP Variants in Viral Replication and the Innate Immune System

Abstract

During viral evolution and adaptation, many viruses have utilized host cellular factors and machinery as their partners. HBx, as a multifunctional viral protein encoded by the hepatitis B virus (HBV), promotes HBV replication and greatly contributes to the development of HBV-associated hepatocellular carcinoma (HCC). HBx interacts with several host factors in order to regulate HBV replication and evolve carcinogenesis. The cellular FADD-like IL-1β-converting enzyme (FLICE)-like inhibitory protein (c-FLIP) is a major factor that functions in a variety of cellular pathways and specifically in apoptosis. It has been shown that the interaction between HBx and c-FLIP determines HBV fate. In this review, we provide a comprehensive and detailed overview of the interplay between c-FLIP and HBV in various environmental circumstances. We describe strategies adapted by HBV to establish its chronic infection. We also summarize the conventional roles of c-FLIP and highlight the functional outcome of the interaction between c-FLIP and HBV or other viruses in viral replication and the innate immune system.

Keywords: HBx; cellular FLIP (c-FLIP); hepatitis B virus; innate immune system; viral FLIP (v-FLIP).

Figure 1

Schematic representation of procaspase-8 and FLIP variants. Structures of v-FLIP, procaspase-8 (a), c-FLIP isoforms and cleaved products (b) are depicted. All proteins commonly share DED1 and DED2 domains. Several post-translational modification sites (phosphorylation and ubiquitination) or caspase-8 cleavage sites on c-FLIP are indicated. c-FLIP: cellular FLIP; v-FLIP: viral FLIP; DED: death-effector domain; NLS: nuclear localization signal; NES: nuclear export signal. This illustration was created with BioRender.com.

Figure 2

Proviral and antiviral roles of FLIP variants and corresponding signaling pathways induced in the presence or absence of inflammatory cytokine. Prior to induction of host innate immunity, c-FLIP enhances HBV transcription and replication by protecting HBx from proteasomal degradation. Additionally, c-FLIP up-regulates HNF1α and HNF4α levels that are essential co-factors for HBV genome expression. The inhibitory transcription factor HNF3β is degraded to facilitate HBV RNA production (left). Following the moderate induction of TNF-α, HBx-p22-FLIP-NEMO ternary complex is formed that further enhances canonical NF-κB pathway by proteasomal degradation of phosphorylated IκB, which amplifies c-FLIP transcription by p50 and p65. This renders antiviral activity of c-FLIP. When TNF-α is highly secreted, c-FLIP is cleaved by caspase-8 to form p22-FLIP which consequently phosphorylates ERK1/2. Activated ERK1/2 accelerates and blocks HNF3β and HNF4α, respectively which impedes HBV transcription from cccDNA. Lastly, high level of TNF-α activates apoptosis by direct activation of cascades. This event is accelerated following the interaction between c-FLIP and HBx (right). HNF: hepatocyte nuclear factor; TNF-α: tumor necrosis factor-α; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; IκB: I-kappa-B; ERK1/2: extracellular signal-regulated kinase 1/2; NEMO: NF-kappa-B essential modulator. This illustration was created with BioRender.com.