Interferon-induced, double-stranded RNA-activated protein kinase

Definition:

IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection. Inhibits viral replication via the integrated stress response (ISR): EIF2S1/eIF-2-alpha phosphorylation in response to viral infection converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting to a shutdown of cellular and viral protein synthesis, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4. Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1). Also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation: phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation. Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding pro-inflammatory cytokines and IFNs. Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6. Can act as both a positive and negative regulator of the insulin signaling pathway (ISP). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes. Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin (By similarity).

References:

[1]. Ben Lu, et al. Novel role of PKR in inflammasome activation and HMGB1 release. Nature. 2012 Aug 30;488(7413):670-4. [Content Brief]

[2]. Jesús Gil, et al. TRAF family proteins link PKR with NF-kappa B activation. Mol Cell Biol. 2004 May;24(10):4502-12. [Content Brief]

[3]. Shensi Shen, et al. Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Mol Cell. 2012 Dec 14;48(5):667-80. [Content Brief]

[4]. Eric Cardin, et al. Nck-1 interacts with PKR and modulates its activation by dsRNA. Biochem Biophys Res Commun. 2008 Dec 5;377(1):231-5. [Content Brief]

[5]. Anthony J Sadler, et al. An antiviral response directed by PKR phosphorylation of the RNA helicase A. PLoS Pathog. 2009 Feb;5(2):e1000311. [Content Brief]

[6]. Il-Hyun Park, et al. PKR-dependent mechanisms of interferon-α for inhibiting hepatitis B virus replication. Mol Cells. 2011 Aug;32(2):167-72. [Content Brief]

[7]. M C Bonnet, et al. PKR stimulates NF-kappaB irrespective of its kinase function by interacting with the IkappaB kinase complex. Mol Cell Biol. 2000 Jul;20(13):4532-42. [Content Brief]

[8]. Ju-Il Kang, et al. PKR protein kinase is activated by hepatitis C virus and inhibits viral replication through translational control. Virus Res. 2009 Jun;142(1-2):51-6. [Content Brief]

[9]. Richard L Bennett, et al. The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G₁ arrest. Cell Cycle. 2012 Jan 15;11(2):407-17. [Content Brief]

[10]. W L Blalock, et al. Multiple forms of PKR present in the nuclei of acute leukemia cells represent an active kinase that is responsive to stress. Leukemia. 2011 Feb;25(2):236-45. [Content Brief]

[11]. San San Lin, et al. A role for protein kinase PKR in the mediation of Epstein-Barr virus latent membrane protein-1-induced IL-6 and IL-10 expression. Cytokine. 2010 May;50(2):210-9. [Content Brief]

[12]. Yuye Li, et al. Protein kinase regulated by dsRNA downregulates the interferon production in dengue virus- and dsRNA-stimulated human lung epithelial cells. PLoS One. 2013;8(1):e55108. [Content Brief]

[13]. Kristina M Okonski, et al. Stress granule formation induced by measles virus is protein kinase PKR dependent and impaired by RNA adenosine deaminase ADAR1. J Virol. 2013 Jan;87(2):756-66. [Content Brief]

[14]. Xuerui Yang, et al. The double-stranded RNA-dependent protein kinase differentially regulates insulin receptor substrates 1 and 2 in HepG2 cells. Mol Biol Cell. 2010 Oct 1;21(19):3449-58. [Content Brief]

[15]. Jin-Hai Chang, et al. Double-stranded RNA-activated protein kinase inhibits hepatitis C virus replication but may be not essential in interferon treatment. Liver Int. 2010 Feb;30(2):311-8. [Content Brief]

[16]. Lumin Zhang, et al. The modulation of hepatitis C virus 1a replication by PKR is dependent on NF-kB mediated interferon beta response in Huh7.5.1 cells. Virology. 2013 Mar 30;438(1):28-36. [Content Brief]

[17]. Cheol-Hee Yoon, et al. New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase triggers Cdc2 polyubiquitination and G2 arrest under genotoxic stresses. EMBO Rep. 2010 May;11(5):393-9. [Content Brief]

[18]. Dongxue Mao, et al. De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation. Am J Hum Genet. 2020 Apr 2;106(4):570-583. [Content Brief]

[19]. Christopher S McAllister, et al. Protein kinase PKR amplification of interferon β induction occurs through initiation factor eIF-2α-mediated translational control. J Biol Chem. 2012 Oct 19;287(43):36384-92. [Content Brief]

[20]. Ai Harashima, et al. Phosphorylation of the NFAR proteins by the dsRNA-dependent protein kinase PKR constitutes a novel mechanism of translational regulation and cellular defense. Genes Dev. 2010 Dec 1;24(23):2640-53. [Content Brief]

[21]. Aristóbolo M Silva, et al. Protein kinase R (PKR) interacts with and activates mitogen-activated protein kinase kinase 6 (MKK6) in response to double-stranded RNA stimulation. J Biol Chem. 2004 Sep 3;279(36):37670-6. [Content Brief]

[22]. William L Blalock, et al. PKR activity is required for acute leukemic cell maintenance and growth: a role for PKR-mediated phosphatase activity to regulate GSK-3 phosphorylation. J Cell Physiol. 2009 Oct;221(1):232-41. [Content Brief]

[23]. Fumihiko Okumura, et al. Activation of double-stranded RNA-activated protein kinase (PKR) by interferon-stimulated gene 15 (ISG15) modification down-regulates protein translation. J Biol Chem. 2013 Jan 25;288(4):2839-47. [Content Brief]

[24]. Kevin A Cassady, et al. The herpes simplex virus type 1 U(S)11 protein interacts with protein kinase R in infected cells and requires a 30-amino-acid sequence adjacent to a kinase substrate domain. J Virol. 2002 Mar;76(5):2029-35. [Content Brief]

[25]. Nora Taghavi, et al. Protein kinase PKR catalytic activity is required for the PKR-dependent activation of mitogen-activated protein kinases and amplification of interferon beta induction following virus infection. Virology. 2012 Jun 5;427(2):208-16. [Content Brief]

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