Hepatitis E Virus Papain-Like Cysteine Protease Inhibits Type I Interferon Induction by Down-Regulating Melanoma Differentiation-Associated Gene 5

Abstract

Upon viral infection, the host cell recognizes the invasion through a number of pattern recognition receptors. Melanoma differentiation associated gene 5 (MDA5) and retinoic acidinducible gene-I (RIG-I) recognize RNA molecules derived from invading viruses, activating downstream signaling cascades, culminating in the induction of the type I interferon. On the other hand, viruses have evolved to evade type I interferon-mediated inhibition. Hepatitis E virus has been shown to encode a few antagonists of type I interferon and it is not surprising that viruses encode multiple mechanisms of viral evasion. In the present study, we demonstrated that HEV PCP strongly down-regulates MDA5-mediated activation of interferon β induction in a dose-dependent manner. Interestingly, MDA5 protein expression was almost completely abolished. In addition, polyinosinic polycytidylic acid (poly(I:C))-and Sendai virus-mediated activation of type I interferon responses were similarly abrogated in the presence of HEV PCP. Furthermore, HEV PCP down-regulates several molecules that play critical roles in the induction of type I IFN expression. Taken together, these data collectively suggest that HEV-encoded PCP is a strong antagonist of type I interferon.

Middle East respiratory syndrome coronavirus-encoded ORF8b strongly antagonizes IFN-β promoter activation: its implication for vaccine design

“…Type I IFN responses are a first line of defense against invading viruses Myoung, 2017a, 2017b;Kang et al, 2018;Kim and Myoung, 2018;Banerjee et al, 2019). There are 16 different type I IFN's that are known to be expressed in humans (Kindler et al, 2016): IFN-α (13 subtypes), IFN-β, IFN-κ, and IFN-ω (1 type each).…”

“…HEK293T cells (4 × 10 5 cells/well) were seeded in a 6-well plate a day before transfection as previously described (Kang et al, 2018;Kim and Myoung, 2018;Park et al, 2019). Briefly, mixtures, containing 500 ng of Interferon (IFN)-β-luc, 100 ng of β-gal expressing plasmid as the internal control, 500 ng of immune gene stimulating plasmid and 1,000 ng of MERS accessary gene encoding or empty plasmid, were transfected using PEI transfection reagent as ratio of 1:2 (DNA: PEI) in 200 μl of opti-MEM (Thermo Fisher Scientific).…”

Methyltransferase of a cell culture-adapted hepatitis E inhibits the MDA5 receptor signaling pathway

“…Construction of expression plasmids of HEV-encoded genes and the host signaling molecules (MDA5, RIG-I, TBK1, IKKε, and IRF3) were described elsewhere (Kang et al, 2018;Kim and Myoung, 2018;Myoung and Min, 2019). Sequences of MeT's of 4 reference strains were codon optimized and synthesized by Bionics.…”

“…To examine if HEV-encoded MeT regulates the MDA5/ RIG-I receptor signaling pathway, luciferase reporter assay was employed as described before (Kang et al, 2018;Kim and Myoung, 2018;Myoung and Min, 2019;Park et al, 2019). Briefly, MeT expressing plasmid was co-transfected into HEK293T cells with IFN-β-Luc/NF-κB-Luc, β-galactosidase…”

“…RIG-I has been reported to bind to relatively short dsRNA's which are blunt-ended with 5'-triphosphates (Kato et al, , 2008. On the contrary, MDA5 does not seem to have strict structural and chemical restrictions, binding to long dsRNA's (Hornung et al, 2006;Pichlmair et al, 2006;Kim and Myoung, 2018;Myoung and Min, 2019). Upon cognate ligand binding, RLR's undergo conformational changes, releasing auto-inhibited caspase activation and recruitment domain (CARD).…”