Journal Article

Targeting Nup358/RanBP2 by a viral protein disrupts stress granule formation

Andino, Raul, Sadasivan, Jibin, Jan, Eric, Vlok, Marli, Nayak, Arabinda, Wang, Xinying

2022

Overview

Viruses have evolved mechanisms to modulate cellular pathways to facilitate infection. One such pathway is the formation of stress granules (SG), which are ribonucleoprotein complexes that assemble during translation inhibition following cellular stress. Inhibition of SG assembly has been observed under numerous virus infections across species, suggesting a conserved fundamental viral strategy. However, the significance of SG modulation during virus infection is not fully understood. The 1A protein encoded by the model dicistrovirus, Cricket paralysis virus (CrPV), is a multifunctional protein that can bind to and degrade Ago-2 in an E3 ubiquitin ligase-dependent manner to block the antiviral RNA interference pathway and inhibit SG formation. Moreover, the R146 residue of 1A is necessary for SG inhibition and CrPV infection in both Drosophila S2 cells and adult flies. Here, we uncoupled CrPV-1A’s functions and provide insight into its underlying mechanism for SG inhibition. CrPV-1A mediated inhibition of SGs requires the E3 ubiquitin-ligase binding domain and the R146 residue, but not the Ago-2 binding domain. Wild-type but not mutant CrPV-1A R146A localizes to the nuclear membrane which correlates with nuclear enrichment of poly(A)+ RNA. Transcriptome changes in CrPV-infected cells are dependent on the R146 residue. Finally, Nup358/RanBP2 is targeted and degraded in CrPV-infected cells in an R146-dependent manner and the depletion of Nup358 blocks SG formation. We propose that CrPV utilizes a multiprong strategy whereby the CrPV-1A protein interferes with a nuclear event that contributes to SG inhibition in order to promote infection.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Antiviral drugs / Argonaute 2 protein / Bees / Binding / Biology and Life Sciences / Biomolecules / Cell Line / Cellular stress response / Coronaviruses / Cytoplasmic Granules - metabolism / Depletion / Development and progression / Domains / Drosophila / Foot & mouth disease / Gene expression / Genetic aspects / Genomes / Granular materials / Hepatitis C / Infections / Influenza / Inhibition / Insects / Kinases / Medicine and Health Sciences / Paralysis / Physiological aspects / Proteins / Ran-binding protein / Research and Analysis Methods / Residues / Respiratory diseases / Ribonucleoproteins / RNA polymerase / RNA-mediated interference / Severe acute respiratory syndrome coronavirus 2 / Stress / Stress Granules / Transcriptomes / Ubiquitin / Ubiquitin-protein ligase / Viral proteins / Viral Proteins - metabolism / Virus diseases / Virus Replication / Virus research / Viruses / West Nile virus