Translation inhibition and stress granules in the antiviral immune response

McCormick, Craig; Khaperskyy, Denys A.

doi:10.1038/nri.2017.63

Cited by 294 publications

(358 citation statements)

References 131 publications

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“…In recent years, SGs have increasingly been seen as important antiviral signaling platforms (2,(4)(5)(6)(7). Several molecules involved in RLR signaling and stress response signaling have been found to localize in SGs (5,(8)(9)(10).…”

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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“…These structures have been identified in plant, yeast, and mammalian cells, and have been characterized microscopically by electron microscopy and immunofluorescence approaches . Stress granules were found to be nonmembranous cytoplasmic structures that usually formed via a multistep process in response to stresses that resulted in translational arrest, such as viral infections, heat, oxidation, and starvation . A recent study has shown that stress granules contain a stable core region surrounded by a dynamic shell‐like structure .…”

Section: The Formation Of Stress Granulesmentioning

confidence: 99%

mRNPs meet stress granules

Sheinberger

Shav‐Tal

2017

FEBS Letters

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Edited by Wilhelm JustStress granules are cytoplasmic structures that form in response to a variety of cellular stresses. They contain mRNAs and many proteins including numerous types of RNA-binding proteins, and have been studied in connection to major cellular events such as protein synthesis as well as disease. Despite the well-known fact that stress granules encapsulate mRNPs (mRNA-protein complexes), much of the research has naturally focused on the protein components of stress granules. The specific details of mRNP entry into and exit from stress granules and the functional reasons for these dynamics are not fully understood. Here, we review studies that have concentrated on the aspects of mRNP accumulation in stress granules and produced quantitative data concerning mRNP/stress granule interactions.

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“…The formation and components of SGs are reviewed in details here [71]. SGs assembly during global translational arrest negatively impact viral genome translation as the SGs reduce the accessibility of translational machinery complexes [72]. Following the relief of translation suppression, the SGs are disassembled via several mechanisms, one of which involves eIF2α dephosphorylation by Growth Arrest and DNA-Damage-inducible 34 (GADD34) protein [73].…”

Section: Zikv Inhibits Cytoplasmic Stress Granules Formationmentioning

confidence: 99%

Endoplasmic reticulum: a focal point of Zika virus infection

et al. 2020

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Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family. It is an arbovirus that can cause congenital abnormalities and is sexually transmissible. A series of outbreaks accompanied by unexpected severe clinical complications have captured medical attention to further characterize the clinical features of congenital ZIKV syndrome and its underlying pathophysiological mechanisms. Endoplasmic reticulum (ER) and ER-related proteins are essential in ZIKV genome replication. This review highlights the subcellular localization of ZIKV to the ER and ZIKV modulation on the architecture of the ER. This review also discusses ZIKV interaction with ER proteins such as signal peptidase complex subunit 1 (SPCS1), ER membrane complex (EMC) subunits, and ER translocon for viral replication. Furthermore, the review covers several important resulting effects of ZIKV infection to the ER and cellular processes including ER stress, reticulophagy, and paraptosis-like death. Pharmacological targeting of ZIKVaffected ER-resident proteins and ER-associated components demonstrate promising signs of combating ZIKV infection and rescuing host organisms from severe neurologic sequelae.

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Translation inhibition and stress granules in the antiviral immune response

Cited by 294 publications

References 131 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

mRNPs meet stress granules

Endoplasmic reticulum: a focal point of Zika virus infection

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