PKR-mediated signaling

PKR-mediated signaling Interferon-induced, double-stranded RNA-activated protein kinase PKR (EIF2AK2) mainly halts cellular protein translation by phosphorylating eIF2α, which blocks the recycling of GDP-eIF2 to GTP-eIF2 required for cap-dependent translation initiation. PKR is constitutively expressed at low level, and its expression is up-regulated by interferon alpha/beta signaling. PKR is mainly localized in the cytoplasm with a small fraction in the nucleus (Tian & Mathews 2001).
PKR was identified in the 1970s (Friedman et al, 1972; Kerr et al., 1977). Its activation is characterized by the shifting of its monomer/dimer equilibrium towards the dimer, with subsequent autophosphorylation (reviewed by Sadler & Williams, 2007; Bou-Nader et al, 2019). Possible activating factors include binding of viral dsRNA to the PKR dsRNA binding domain (reviewed by Nallagatla et al, 2011), as well as cellular proteins (ISG15, PACT, DCP1A) and heparin (Patel & Sen, 1998; Dougherty et al., 2014; George et al., 1996; Fasciano et al., 2005; reviewed by Zhang et al, 2021). General translation shutdown by PKR can therefore be promoted by both viral infection and the integrated response of the cell to stress stimuli (reviewed by Pizzinga et al, 2019; Costa-Mattioli & Walter, 2020). Several cellular inhibitors of PKR activation and eIF2α phosphorylation by PKR have been identified and binding of PKR to viral proteins from RNA viruses (e.g. HIV, influenza A, RSV) has also been shown to contribute to inhibition (reviewed by Cesaro & Michiels, 2021). In addition to its role in translation shutdown via eIF2α, PKR affects translation through NFAR protein phosphorylation; it can also phosphorylate RNA helicase A, CDC2, and MKK6, thus modulating RNA metabolism, G2 arrest, and p38 MAPK activation. Finally, PKR can bind to TRAF proteins, the IkappaB kinase complex, GSK-3beta, and several inflammasome components leading to NF-kappa B activation, tau phosphorylation, apoptosis, and inflammasome activation (reviewed by Gil & Esteban, 2000; Garcia et al, 2007; Pindel & Sadler, 2011; Marchal et al, 2014; Yim & Williams, 2014; McKey et al, 2021).