Dose-dependent inhibition of melanoma differentiation-associated gene 5-mediated activation of type I interferon responses by methyltransferase of hepatitis E virus

Hepatitis E virus (HEV) accounts for 20 million infections in humans worldwide. In most cases, the infections are self-limiting while HEV genotype 1 infection cases may lead to lethal infections in pregnant women (~ 20% fatality). The lack of small animal models has hampered detailed analysis of virus-host interactions and HEV-induced pathology. Here, by employing a recently developed culture-adapted HEV, we demonstrated that methyltransferase, a nonstructural protein, strongly inhibits melanoma differentiation-associated gene 5 (MDA5)-mediated activation of type I interferon responses. Compared to uninfected controls, HEV-infected cells display significantly lower levels of IFN-β promoter activation when assessed by luciferase assay and RT-PCR. HEV genome-wide screening showed that HEV-encoded methyltransferase (MeT) strongly inhibits MDA5-mediated transcriptional activation of IFN-β and NF-κB in a dose-responsive manner whether or not it is expressed in the presence/ absence of a tag fused to it. Taken together, current studies clearly demonstrated that HEV MeT is a novel antagonist of MDA5-mediated induction of IFN-β signaling.