Reactome | PKR-mediated signaling

PKR-mediated signaling

Stable Identifier

R-HSA-9833482

DOI

10.3180/R-HSA-9833482.1

Type

Pathway

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Click the image above or here to open this pathway in the Pathway Browser

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