Inhibition of MAVS Aggregation-Mediated Type-I Interferon Signaling by Foot-and-Mouth Disease Virus VP3.

Pathum Ekanayaka,Jong-Hyeon Park,Kiramage Chathuranga,Jong-Soo Lee,Byeong-Hoon Lee,Asela Weerawardhana

doi:10.3390/v13091776

Pathum Ekanayaka, Jong-Hyeon Park + Show 4 more

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https://doi.org/10.3390/v13091776

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Abstract

As a structural protein of the Foot-and-mouth disease virus (FMDV), VP3 plays a vital role in virus assembly and inhibiting the interferon (IFN) signal transduction to promote FMDV replication. Previous studies demonstrated that FMDV VP3 blocks the type-I IFN response by inhibiting the mRNA expression of the mitochondrial antiviral-signaling protein (MAVS); however, the underlying mechanism is poorly understood. Here, we describe the specificity of FMDV VP3 interaction with the transmembrane (TM) domain of MAVS as FMDV driven type-I IFN inhibitory mechanism for its effective replication. The TM domain of MAVS governs the mitochondria localization of MAVS, and it is a key factor in type-I IFN signaling transduction via MAVS aggregation. Thereby, the interaction of FMDV VP3 with the TM domain of MAVS leads to the inhibition of MAVS mitochondria localization, self-association, and aggregation, resulting in the suppression of type-I IFN response. Collectively, these results provide a clear understanding of a key molecular mechanism used by the FMDV VP3 for the suppression of IFN responses via targeting MAVS.

Highlights

Foot-and-mouth disease (FMD) virus is a highly contagious and economically devastating virus that infects wild and domestic cloven-hoofed animals and poses a major threat to the livestock industry worldwide [1,2,3]
The Foot-and-mouth disease virus (FMDV) VP3 structural protein plays a significant role in suppressing antiviral responses [46,47], but the underlying molecular mechanism remains unclear
To evaluate the role of FMDV VP3 in innate immune responses, we used VSV-green fluorescent protein (GFP) to infect FMDV VP3 stably expressing RAW264.7 cells (Figure 1A–C), HEK293T cells transiently transfected with FMDV VP3 (Figure 1D–F), and PK15 cells transiently transfected with

Summary

Introduction

Foot-and-mouth disease (FMD) virus is a highly contagious and economically devastating virus that infects wild and domestic cloven-hoofed animals and poses a major threat to the livestock industry worldwide [1,2,3]. The PRRs, mainly retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), detect initial virus infection by recognizing viral RNA in the cytoplasm of the cells [13]. Mitochondrial localization of MAVS is necessary for proper activation of the protein; once activated, MAVS aggregates by forming a functional prion-like structure on mitochondria [20] This structure serves as a platform to create the MAVS signalosome, which primes the activation of TBK1 and IKK-ε [20,21,22], which locates downstream to the MAVS in the type-I IFN pathway. This leads, in turn, to the activation of downstream molecules IRF3, IRF7, and NF-κB (activated via IKK) of the type-I IFN signaling cascade, which elicits antiviral responses through the production of IFNs [14,15,16,17]

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