Foot-and-Mouth Disease Virus 3C Protease Cleaves NEMO To Impair Innate Immune Signaling

Abstract

Foot-and-mouth disease is a highly contagious viral illness of wild and domestic cloven-hoofed animals. The causative agent, foot-and-mouth disease virus (FMDV), replicates rapidly, efficiently disseminating within the infected host and being passed on to susceptible animals via direct contact or the aerosol route. To survive in the host, FMDV has evolved to block the host interferon (IFN) response. Previously, we and others demonstrated that the leader proteinase (L pro ) of FMDV is an IFN antagonist. Here, we report that another FMDV-encoded proteinase, 3C pro , also inhibits IFN-α/β response and the expression of IFN-stimulated genes. Acting in a proteasome- and caspase-independent manner, the 3C pro of FMDV proteolytically cleaved nuclear transcription factor kappa B (NF-κB) essential modulator (NEMO), a bridging adaptor protein essential for activating both NF-κB and interferon-regulatory factor signaling pathways. 3C pro specifically targeted NEMO at the Gln 383 residue, cleaving off the C-terminal zinc finger domain from the protein. This cleavage impaired the ability of NEMO to activate downstream IFN production and to act as a signaling adaptor of the RIG-I/MDA5 pathway. Mutations specifically disrupting the cysteine protease activity of 3C pro abrogated NEMO cleavage and the inhibition of IFN induction. Collectively, our data identify NEMO as a substrate for FMDV 3C pro and reveal a novel mechanism evolved by a picornavirus to counteract innate immune signaling.

Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage

“…Previous studies have reported that picornaviruses exert various strategies to evade host innate immune responses through certain viral proteins, such as L pro , VP2, VP3, 2A pro , 2C pro , 3A pro , and 3C pro (17,18,(25)(26)(27)(28)(29)(30)(31). In this study, we found that the overexpression of SVV proteins VP2, 3C pro , and 3D reduced Sev-induced IFN-␤ production (Fig.…”

“…Foot-and-mouth disease virus (FMDV) 3C pro and hepatitis A virus (HAV) 3C pro cleave NEMO to impair type I IFN production (30,31). Enterovirus 3C pro can target RIG-I, MAVS, TRIF, and IRF7 for cleavage to evade host antiviral innate immunity (18).…”

“…FMDV infection restricts the expression of RIG-I, DMA5, and MAVS to attenuate host innate immune responses (18,27,29). FMDV can also target NEMO to cleave it to inhibit NF-B-and IRF3-mediated IFN production (30). HAV ablates the RLRand TLR-mediated type I IFN response by cleaving MAVS and NEMO (31,42).…”

Hepatitis A Virus 3C Protease Cleaves NEMO To Impair Induction of Beta Interferon

“…This also could explain the striking observation that acute HAV infection is associated with a very limited type I IFN response, despite the persistence of intrahepatic viral RNA (8). Previously, we reported that NEMO is a substrate for 3C pro of another picornavirus, foot-and-mouth disease virus (19). Recently, 3C…”

Enterovirus 68 3C Protease Cleaves TRIF To Attenuate Antiviral Responses Mediated by Toll-Like Receptor 3

“…pro of foot-and-mouth disease virus cleaves NF-B essential modulator (NEMO) to impair innate immune signaling (40). The 3C pro precursors, 3ABC and 3CD, of hepatitis A virus cleave IPS-1 (41) and TRIF (42) to block antiviral signaling.…”