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Research Project: Intervention Strategies to Support the Global Control and Eradication of Foot-and-Mouth Disease Virus (FMDV)

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Title: FMDV leader protease cleaves G3BP1 and G3BP2 and inhibits stress granule formation

Author
item VISSER, LINDA - Utrecht University
item Medina, Gisselle
item RABOUW, HUIB - Utrecht University
item DE GROOT, RAUL - Utrecht University
item LANGEREIS, MARTIJN - Utrecht University
item De Los Santos, Teresa
item VAN KUPPEVELD, FRANK - Utrecht University

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/26/2018
Publication Date: 11/7/2018
Citation: Visser, L.J., Medina, G.N., Rabouw, H.H., De Groot, R.J., Langereis, M.A., De los Santos, T.B., Van Kuppeveld, F.J. 2018. FMDV leader protease cleaves G3BP1 and G3BP2 and inhibits stress granule formation. Journal of Virology. https://doi.org/10.1128/JVI.00922-18.
DOI: https://doi.org/10.1128/JVI.00922-18

Interpretive Summary: In this paper we have identified a new mechanism by which the leader protein of FMDV inhibits the stress response induced in a cell to protect itself from pathogens. We demonstrate that the leader protein degrades some specific components of stress granules, which are small vesicles inside the cell that protect cellular RNAs and proteins. In this way, the virus uses another mechanism to highjack the cellular machinery for its own benefit.

Technical Abstract: The picornavirus foot-and-mouth disease virus (FMDV, genus aphthovirus), one of the most notorious pathogens in global livestock industry, has multiple ways of suppressing the type I IFN response, but it is largely unknown whether and how it suppresses the integrated stress response. Here, we show that the stress response is suppressed during FMDV infection. Using a chimeric recombinant EMCV, in which we functionally replaced the endogenous stress response antagonist by FMDV proteases Lpro or 3Cpro, we demonstrate an essential role for Lpro in suppressing stress granule (SG) formation. Consistently, infection with a recombinant FMDV lacking Lpro expression resulted in SG formation. Additionally, we show that Lpro cleaves the known SG scaffold proteins G3BP1 and G3BP2, but not TIA-1. We demonstrate that the Lpro of the closely related equine rhinitis A virus (ERAV) also cleaves G3BP1/2 and also suppresses SG formation, indicating that aphthoviruses suppress the stress response via a conserved mechanism. Neither FMDV or ERAV Lpro interfered with phosphorylation of PKR or eIF2a, indicating that Lpro does not affect SG formation by inhibiting the PKR-triggered signaling cascade. Taken together, our data suggest that aphthoviruses actively target scaffolding proteins G3BP1/2 and antagonize SG formation to modulate the integrated stress response.