STRESS GRANULE FORMATION INDUCED BY MEASLES VIRUS IS PROTEIN KINASE PKR DEPENDENT AND IMPAIRED BY RNA ADENOSINE DEAMINASE ADAR1.

Tuesday, 3rd of September 2013

[source]Journal of Virology [|source]

This study establishes that stress granules (SG) formation induced by measles virus (MV) infection is modulated in an opposing manner by ADAR1 and PKR. SG formation is impaired by ADAR1, just as the activation of PKR and induction of IFN-β likewise are impaired by ADAR1. But MV-  induced SG formation is dependent upon PKR. The opposing roles of ADAR1 and PKR suggest that these proteins may likely contribute to the dynamic oscillation of SG formation characteristic of the cellular response to virus infection. This report illustrates the delicate balance between PKR and ADAR1 and add to a growing body of evidence that despite being an IFN-stimulated gene, ADAR1 in some instances both suppresses host responses characteristic of virus infection and enhances virus growth. If interested in more details then visit:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554044/

 

Abstract

Adenosine deaminase acting on RNA 1 (ADAR1), an interferon (IFN)-inducible double-stranded (ds) RNA-specific adenosine deaminase, downregulates host innate responses, including activation of the dsRNA-dependent protein kinase (PKR) and induction of IFN-β mRNA. Conversely, PKR amplifies IFN-β induction by measles virus (MV) and inhibits virus protein synthesis. Formation of stress granules (SGs), cytoplasmic aggregates of stalled translation complexes and RNA-binding proteins, is a host response to virus infection mediated by translation initiation factor eIF2α phosphorylation. We examined the roles of PKR and ADAR1 in SG formation using HeLa cells stably deficient in either PKR (PKR^kd) or ADAR1 (ADAR1^kd) compared to control (CON^kd) cells. Infection with either wild-type (WT) MV or an isogenic mutant lacking C protein expression (C^ko) comparably induced formation of SG in ADAR1^kd cells, whereas only the C^ko mutant was an efficient inducer in control cells. Both ADAR1 and PKR colocalized with SG following infection. MV-induced; SG formation was PKR dependent but impaired by ADAR1. Complementation of ADAR1^kd cells by expression of either p150 WT isoform or the p150 Zα (Y177A) Z-DNA-binding mutant of ADAR1 restored suppression of host responses, including SG formation and PKR activation. In contrast, neither the p110 WT isoform nor the p150 catalytic (H910A, E912A) mutant of ADAR1 complemented the ADAR1^kd phenotype. These results further establish ADAR1 as a suppressor of host innate responses, including activation of PKR and the subsequent SG response.