PKR

PKR

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 (PubMed:18835251, PubMed:19507191, PubMed:19189853, PubMed:21123651, PubMed:21072047, PubMed:22948139, PubMed:23229543, PubMed:22381929).
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 (PubMed:19189853, PubMed:21123651, PubMed:22948139, PubMed:23229543).
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) (PubMed:11836380, PubMed:19189853, PubMed:20171114, PubMed:19840259, PubMed:21710204, PubMed:23115276, PubMed:23399035).
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 (PubMed:11836380, PubMed:22214662, PubMed:19229320).
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 (PubMed:20395957).
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 (PubMed:22948139, PubMed:23084476, PubMed:23372823).
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 (PubMed:10848580, PubMed:15121867, PubMed:15229216).
Can act as both a positive and negative regulator of the insulin signaling pathway (ISP) (PubMed:20685959).
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) (PubMed:20685959).
Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes (PubMed:22801494).
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).

Acute inflammatory response Source: Ensembl
HRI-mediated signaling Source: UniProtKB
Integrated stress response signaling Source: UniProtKB
Iron ion homeostasis Source: Ensembl
Macrophage differentiation Source: Ensembl
Negative regulation of cell population proliferation Source: Ensembl
Negative regulation of hemoglobin biosynthetic process Source: UniProtKB
Negative regulation of translational initiation by iron Source: UniProtKB
Phagocytosis Source: Ensembl
Protein autophosphorylation Source: UniProtKB
Protoporphyrinogen IX metabolic process Source: Ensembl
Regulation of eIF2 alpha phosphorylation by heme Source: Ensembl
Response to iron ion starvation Source: UniProtKB

Cytoplasm

Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome (LEMSPAD):
A disorder characterized by delayed motor development, speech delay with dysarthria, hypertonia, progressive spasticity, hyperreflexia, and bradykinesia. Cognition is normal. Patients manifest anxiety and attention deficit-hyperactivity disorder.

Activated by autophosphorylation; phosphorylated predominantly on serine and threonine residues, but also on tyrosine residues. Autophosphorylation at Thr-488 is required for kinase activation. The active autophosphorylated form apparently is largely refractory to cellular heme fluctuations.