Abstract
Cells respond to viral infections through sensors that detect non-self-molecules, and through effectors, which can have direct antiviral activities or adapt cell physiology to limit viral infection and propagation. Eukaryotic translation initiation factor 2 alpha kinase 2, better known as PKR, acts as both a sensor and an effector in the response to viral infections. After sensing double-stranded RNA molecules in infected cells, PKR self-activates and majorly exerts its antiviral function by blocking the translation machinery and inducing apoptosis. The antiviral potency of PKR is emphasized by the number of strategies developed by viruses to antagonize the PKR pathway. In this review, we present an update on the diversity of such strategies, which range from preventing double-stranded RNA recognition upstream from PKR activation, to activating eIF2B downstream from PKR targets.
Highlights
PKR: A Cornerstone in the Integrated Stress ResponseThe integrated stress response (ISR) is a signaling pathway that optimizes the cellular response to stress and aims to restore homeostasis after different types of stress (Pakos-Zebrucka et al, 2016)
It relies on the detection of cellular stresses by 4 protein kinases, which are referred to as eIF2α kinases (EIF2AK) because they phosphorylate a common target: eukaryotic translation initiation factor 2 subunit alpha (EIF2S1 or eIF2α). eIF2α is a subunit of eIF2, which contributes to the formation of the ternary mRNA translation initiation complex
Acting Upstream or Downstream From the Pathway?. It would look more effective for viral proteins to act upstream from PKR activation, by shielding dsRNA
Summary
PKR: A Cornerstone in the Integrated Stress ResponseThe integrated stress response (ISR) is a signaling pathway that optimizes the cellular response to stress and aims to restore homeostasis after different types of stress (Pakos-Zebrucka et al, 2016). A key mechanism used by viral proteins to inhibit PKR-mediated antiviral response is hiding or sequestering dsRNA molecules that would otherwise activate PKR. Acts by triggering RNA degradation (Gao et al, 2021; Zhao et al, 2021) Upregulation of GADD34, a subunit guiding PP1 to dephosphorylate eIF2α (Wang et al, 2009) Accessory dsRNA-binding protein.
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