Foot-and-mouth disease virus induces lysosomal degradation of host protein kinase PKR by 3C proteinase to facilitate virus replication

Li, Chuntian; Zhu, Zixiang; Du, Xiongming; Cao, Weijun; Yang, Fan; Zhang, Xiangle; Feng, Huanhuan; Li, Dan; Zhang, Keshan; Liu, Xiangtao; Zheng, Haixue

doi:10.1016/j.virol.2017.06.023

Cited by 45 publications

(42 citation statements)

References 43 publications

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“…SG formation is induced upon the activation of eIF2␣ kinases, such as PKR and PERK. While enterovirus infection induces PKR activation, leading to an increase in both phosphorylated PKR (p-PKR) and p-eIF2␣ levels (55,56), FMDV infection was shown to block the activation of this pathway (57), possibly via 3C pro -dependent lysosomal degradation of PKR (57). It has also been reported that the titers of FMDV LLV can be rescued in PKR knockout cells (58), hinting at a possible role for L pro in suppressing PKR signaling.…”

Section: Discussionmentioning

confidence: 99%

Foot-and-Mouth Disease Virus Leader Protease Cleaves G3BP1 and G3BP2 and Inhibits Stress Granule Formation

Visser

Medina

Rabouw

et al. 2019

J Virol

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Like other viruses, the picornavirus foot-and-mouth disease virus (FMDV; genus Aphthovirus), one of the most notorious pathogens in the global livestock industry, needs to navigate antiviral host responses to establish an infection. There is substantial insight into how FMDV suppresses the type I interferon (IFN) response, but it is largely unknown whether and how FMDV modulates the integrated stress response. Here, we show that the stress response is suppressed during FMDV infection. Using a chimeric recombinant encephalomyocarditis virus (EMCV), in which we functionally replaced the endogenous stress response antagonist by FMDV leader protease (L pro ) or 3C pro , we demonstrate an essential role for L pro in suppressing stress granule (SG) formation. Consistently, infection with a recombinant FMDV lacking L pro resulted in SG formation. Additionally, we show that L pro cleaves the known SG scaffold proteins G3BP1 and G3BP2 but not TIA-1. We demonstrate that the closely related equine rhinitis A virus (ERAV) L pro also cleaves G3BP1 and G3BP2 and also suppresses SG formation, indicating that these abilities are conserved among aphthoviruses. Neither FMDV nor ERAV L pro interfered with phosphorylation of RNAdependent protein kinase (PKR) or eIF2␣, indicating that L pro does not affect SG formation by inhibiting the PKR-triggered signaling cascade. Taken together, our data suggest that aphthoviruses actively target scaffolding proteins G3BP1 and G3BP2 and antagonize SG formation to modulate the integrated stress response. IMPORTANCE The picornavirus foot-and-mouth disease virus (FMDV) is a notorious animal pathogen that puts a major economic burden on the global livestock industry. Outbreaks have significant consequences for animal health and product safety. Like many other viruses, FMDV must manipulate antiviral host responses to establish infection. Upon infection, viral double-stranded RNA (dsRNA) is detected, which results in the activation of the RNA-dependent protein kinase (PKR)-mediated stress response, leading to a stop in cellular and viral translation and the formation of stress granules (SG), which are thought to have antiviral properties. Here, we show that FMDV can suppress SG formation via its leader protease (L pro ). Simultaneously, we observed that L pro can cleave the SG scaffolding proteins G3BP1 and G3BP2. Understanding the molecular mechanisms of the antiviral host response evasion strategies of FMDV may help to develop countermeasures to control FMDV infections in the future.

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Section: Discussionmentioning

confidence: 99%

Foot-and-Mouth Disease Virus Leader Protease Cleaves G3BP1 and G3BP2 and Inhibits Stress Granule Formation

Visser

Medina

Rabouw

et al. 2019

J Virol

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“…The commercial antibodies used in this study include an anti-Myc monoclonal antibody (Santa Cruz Biotechnology, Dallas, TX, USA), an anti-FLAG monoclonal antibody (Santa Cruz Biotechnology), an anti-IRF3 monoclonal antibody (Cell Signaling Technology, Beverly, MA, USA), an anti-P-IRF3 monoclonal antibody (Cell Signaling Technology), an anti-DDX1 polyclonal antibody (Abcam, Cambridge, MA, USA), and an anti-b-actin monoclonal antibody (Santa Cruz Biotechnology). An anti-VP1 polyclonal antibody was prepared in our laboratory (Li et al 2017). Anti-3D polyclonal antibody (500 lg/mL) was produced in rabbit by immunization with FMDV 3D protein.…”

Section: Plasmids and Antibodiesmentioning

confidence: 99%

The DEAD-Box RNA Helicase DDX1 Interacts with the Viral Protein 3D and Inhibits Foot-and-Mouth Disease Virus Replication

et al. 2019

Self Cite

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Foot-and-mouth disease virus (FMDV) can infect domestic and wild cloven-hoofed animals. The non-structural protein 3D plays an important role in FMDV replication and pathogenesis. However, the interaction partners of 3D, and the effects of those interactions on FMDV replication, remain incompletely elucidated. In the present study, using the yeast two-hybrid system, we identified a porcine cell protein, DEAD-box RNA helicase 1 (DDX1), which interacted with FMDV 3D. The DDX1-3D interaction was further confirmed by co-immunoprecipitation experiments and an indirect immunofluorescence assay (IFA) in porcine kidney 15 (PK-15) cells. DDX1 was reported to either inhibit or facilitate viral replication and regulate host innate immune responses. However, the roles of DDX1 during FMDV infection remain unclear. Our results revealed that DDX1 inhibited FMDV replication in an ATPase/helicase activity-dependent manner. In addition, DDX1 stimulated IFN-b activation in FMDV-infected cells. Together, our results expand the body of knowledge regarding the role of DDX1 in FMDV infection.Keywords Foot-and-mouth disease virus (FMDV) Á Interaction Á DEAD-box RNA helicase 1 (DDX1) Á Antiviral function Á Interferon Electronic supplementary material The online version of this article (https://doi.

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“…Degradation of PKR by viruses is a less documented method of regulating PKR. To date PKR degradation has been reported in six RNA viruses: Toscana virus (TOSV) (29), Rift Valley fever virus (RVFV) (30-32), poliovirus (33, 34), foot-and-mouth disease virus (FMDV) (35, 36), encephalomyocarditis virus (EMCV, strain mengovirus) (37, 38), and enterovirus 71 (39). RVFV and TOSV both degrade PKR via proteasomal mechanisms involving a viral nonstructural protein (NSs) (32, 40, 41).…”

Section: Introductionmentioning

confidence: 99%

“…The mechanism for PKR proteasomal degradation by NSs has not been described for TOSV (40). FMDV uses the other major cellular protein degradation pathway, the lysosome, to degrade PKR during infection (36). Though the mechanism is unclear, expression of the major FMDV protease 3C pro is required for PKR degradation by the lysosome.…”

Section: Introductionmentioning

confidence: 99%

Enhanced replication of mouse adenovirus type 1 following virus-induced degradation of protein kinase R (PKR)

Goodman

Pretto

Krepostman

et al. 2019

Preprint

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Foot-and-mouth disease virus induces lysosomal degradation of host protein kinase PKR by 3C proteinase to facilitate virus replication

Cited by 45 publications

References 43 publications

Foot-and-Mouth Disease Virus Leader Protease Cleaves G3BP1 and G3BP2 and Inhibits Stress Granule Formation

Foot-and-Mouth Disease Virus Leader Protease Cleaves G3BP1 and G3BP2 and Inhibits Stress Granule Formation

The DEAD-Box RNA Helicase DDX1 Interacts with the Viral Protein 3D and Inhibits Foot-and-Mouth Disease Virus Replication

Enhanced replication of mouse adenovirus type 1 following virus-induced degradation of protein kinase R (PKR)

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