Abstract
Decreased expression of NKG2D ligands on HBV-infected human hepatoma cells impairs NK cells lysis. However, which components of HBV exert this effect and the precise mechanisms need to be further investigated. In the present study, we observed that the HBx and HBc genes significantly down-regulated MICA expression. Through analysis with the chromatin immunoprecipitation assay, we found that HBV infection promotes the expression of transcription factors GATA-2 and GATA-3, which specifically suppressed MICA/B expression by directly binding to the promoter region of MICA/B. HBx protein, acting as a co-regulator, forms a tripolymer with GATA2 and GATA3, thus promotes the GATA-2 or GATA-3-mediated of MICA/B suppression. HBc protein inhibits MICA/B expression via directly binding to the CpG island in the MICA/B promoter. Thus, our study identified the novel role of transcription factors GATA-2 and GATA-3 in suppressing MICA/B expression and clarified the mechanisms of HBx and HBc in downregulation of MICA/B expression. These findings provide novel mechanisms for the contribution of HBV to hepatoma cells escape from NK cell surveillance.
Highlights
Natural killer (NK) cells represent the main effector population of the innate immune system in the defense against virus infection and tumors [1, 2]
We explored the regulatory role of Hepatitis B virus (HBV) infection in the expression of NKG2D ligands, including MICA, MICB, ULBP1, ULBP2 and ULBP3, on HepG2, Figure 1: HBV+ hepatoma cells express lower levels of NKG2D ligands and are less susceptible to NK lysis than HBVhepatoma cells
We found for the first time that HBV infection could promote the expression of transcription factors GATA-2 and GATA-3, which suppressed MICA/B expression via directly binding to the MICA/B promoter
Summary
Natural killer (NK) cells represent the main effector population of the innate immune system in the defense against virus infection and tumors [1, 2]. NK cells express a variety of activating and inhibitory receptors which control the function of NK cells [3]. As a potent activating receptor, the NKG2D receptor plays an important role in the control of viral infections and tumorigenesis through recognizing its ligands, including MICA, MICB and ULBP1-4 in humans and Rae-1, H60 and MULT1 in mice [4]. Viruses have evolved various mechanisms to counteract NKG2D-dependent immune responses. MCMV m152-encoded gp decreases the surface expression of H60 and Rae-1 to inhibit NK cell cytotoxicity. HCMV-encoded soluble proteins, UL16 and UL142, markedly reduce cell surface levels of NKG2D ligands and compromise the efficacy of NK cell responses [5]. A better understanding of the regulatory mechanism of NKG2D and its ligands during virus infection and tumorigenesis is needed
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