PKR-mediated signaling

Stable Identifier
Homo sapiens
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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).
Literature References
PubMed ID Title Journal Year
34901029 ISGylation in Innate Antiviral Immunity and Pathogen Defense Responses: A Review

Li, J, Zhang, M, Zhou, F, Zeng, L, Yan, H, Liu, T, Huang, J, Wang, F

Front Cell Dev Biol 2021
34759908 Inhibition of PKR by Viruses

Michiels, T, Cesaro, T

Front Microbiol 2021
30770398 The search for a PKR code-differential regulation of protein kinase R activity by diverse RNA and protein regulators

Gordon, JM, Bou-Nader, C, Henderson, FE, Zhang, J

RNA 2019
34854899 PHOrming the inflammasome: phosphorylation is a critical switch in inflammasome signalling

Bezbradica, JS, McKee, CM, Fischer, FA, Coll, RC

Biochem Soc Trans 2021
17451862 The dsRNA protein kinase PKR: virus and cell control

Esteban, M, Meurs, EF, García, MA

Biochimie 2007
17969452 Structure and function of the protein kinase R

Sadler, AJ, Williams, BR

Curr Top Microbiol Immunol 2007
24382890 mRNA decapping enzyme 1a (Dcp1a)-induced translational arrest through protein kinase R (PKR) activation requires the N-terminal enabled vasodilator-stimulated protein homology 1 (EVH1) domain

Dougherty, JD, Lloyd, RE, Reineke, LC

J Biol Chem 2014
11232238 Induction of apoptosis by the dsRNA-dependent protein kinase (PKR): mechanism of action

Esteban, M, Gil, J

Apoptosis 2000
21166592 The role of protein kinase R in the interferon response

Sadler, A, Pindel, A

J Interferon Cytokine Res 2011
196217 Nature of inhibitor of cell-free protein synthesis formed in response to interferon and double-stranded RNA

Hovanessian, AG, Brown, RE, Kerr, IM

Nature 1977
4345494 Mechanism of interferon action: inhibition of viral messenger ribonucleic acid translation in L-cell extracts

Friedman, RM, Metz, DH, Ball, LA, Esteban, RM, Kerr, IM, Tovell, DR

J Virol 1972
24905201 Protein kinase R and the inflammasome

Yim, HC, Williams, BR

J Interferon Cytokine Res 2014
32327570 The integrated stress response: From mechanism to disease

Walter, P, Costa-Mattioli, M

Science 2020
11134010 Functional characterization of and cooperation between the double-stranded RNA-binding motifs of the protein kinase PKR

Tian, B, Mathews, MB

J Biol Chem 2001
9687506 PACT, a protein activator of the interferon-induced protein kinase, PKR

Patel, RC, Sen, GC

EMBO J 1998
21145228 Regulation of innate immunity through RNA structure and the protein kinase PKR

Toroney, R, Bevilacqua, PC, Nallagatla, SR

Curr Opin Struct Biol 2011
24522206 The impact of PKR activation: from neurodegeneration to cancer

García-García, JA, Garcia, MA, Delgado, JR, Comino, A, Rivas, C, Marchal, JA, Lopez, GJ, Conde, V, Aranda, FM, Peran, M, Esteban, M

FASEB J 2014
8661426 Characterization of the heparin-mediated activation of PKR, the interferon-inducible RNA-dependent protein kinase

McCormack, SJ, Svahn, CM, George, CX, Samuel, CE, Thomis, DC

Virology 1996
31755249 The cell stress response: extreme times call for post-transcriptional measures

Dezi, V, Poyry, T, Ramakrishna, M, Mordue, R, Garland, GD, Willis, AE, Mulroney, TE, Harvey, RF, Sfakianos, A, Monti, M, Pizzinga, M

Wiley Interdiscip Rev RNA 2020
15752359 Identification of the heparin-binding domains of the interferon-induced protein kinase, PKR

Handy, I, Fasciano, S, Hutchins, B, Patel, RC

FEBS J 2005
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