Constitutively Active MDA5 Proteins Are Inhibited by Paramyxovirus V Proteins

Abstract

Excessive interferon (IFN) production and signaling can lead to immunological and developmental defects giving rise to autoimmune diseases referred to collectively as "type I interferonopathies." A subset of these diseases is caused by monogenic mutations affecting proteins involved in nucleic acid sensing, homeostasis, and metabolism. Interferonopathic mutations in the cytosolic antiviral sensor MDA5 render it constitutively hyperactive, resulting in chronic IFN production and IFN-stimulated gene expression. Few therapeutic options are available for patients with interferonopathic diseases, but a large number of IFN evasion and antagonism strategies have evolved in viral pathogens that can counteract IFN production and signaling to enhance virus replication. To test the hypothesis that these natural IFN suppressors could be used to subdue the activity of interferonopathic signaling proteins, hyperactive MDA5 variants were assessed for susceptibility to a family of viral MDA5 inhibitors. In this study, Paramyxovirus V proteins were tested for their ability to counteract constitutively active MDA5 proteins. Results indicate that the V proteins are able to bind to and disrupt the signaling activity of these MDA5 proteins, irrespective of their specific mutations, reducing IFN production and IFN-stimulated gene expression to effectively suppress the hyperactive antiviral response.

Innate Inhibiting Proteins Enhance Expression and Immunogenicity of Self-Amplifying RNA

“…In this study, we screened a library of saRNA constructs with cis -encoded IIPs and determined the effect on protein expression and immunogenicity. We chose a range of IIPs based on their varied targets in the type I IFN pathway ( Figure 1 ; Table 1 ), including the herpes simplex virus 2 (HSV-2) US1, 19 herpes simplex virus 1 (HSV-1) US1 and US11, 20 , 21 Orf virus OV20.0L, 22 , 23 bovine viral diarrhea virus (BVDV) Npro, 24 , 25 parainfluenza virus 5 (PIV-5) V, 26 , 27 Middle East respiratory syndrome coronavirus (MERS CoV) M, 28 , 29 , 30 and ORF4a, 31 , 32 Langat virus NS5, 33 , 34 and influenza virus NS1 proteins. 35 We characterized the library of saRNA IIP constructs in vitro in mouse, rabbit, nonhuman primate, and human cells with varying IFN competencies, as well as in vivo for both intracellular and secreted protein expression.…”

MDA5 cleavage by the Leader protease of foot-and-mouth disease virus reveals its pleiotropic effect against the host antiviral response

“…Paramyxovirus V proteins interact with MDA5 and LGP2 abolishing MDA5-dependent signaling 53 , 54 and its co-activation by LGP2 55 . These proteins have been shown to disrupt chronic signaling and antiviral activity of MDA5 proteins with mutations that confer hyperactive signaling profiles in patients with interferonopathic disorders 56 .…”

A Comprehensive Review of Autophagy and Its Various Roles in Infectious, Non-Infectious, and Lifestyle Diseases: Current Knowledge and Prospects for Disease Prevention, Novel Drug Design, and Therapy

“…All of these viral events are related to autophagy and can provide directions for future therapies for Chikungunya (CHIKV), DENV, and Zika virus (ZIKV) infections. Autophagy has a pivotal role in viral diseases such as bird flu [32], swine fever [33], Ebola virus disease [20], ZIKV infection [34,35], SARS [36], CHIKV infection [37], DENV infection [38], viral encephalitis [39], CCHF [40], Hendra virus (HeV) infection [41], Nipah virus (NiV) infection [42], and the West Nile virus (WNV) infection [43]. Apart from these, other viral diseases, such as rabies, rotavirus enteritis, and smallpox, have already posed a serious threat to human life [44,45,46,47,48].…”