EIF2AK2
Description
The EIF2AK2 (eukaryotic translation initiation factor 2 alpha kinase 2) is a protein-coding gene located on chromosome 2.
EIF2AK2, also known as protein kinase R (PKR), interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2), is an enzyme that in humans is encoded by the EIF2AK2 gene on chromosome 2. PKR is a serine/tyrosine kinase that is 551 amino acids long. PKR is inducible by various mechanisms of stress and protects against viral infections. It also has a role in several signaling pathways.
== Mechanism of action == Protein kinase-R is activated by double-stranded RNA (dsRNA), introduced to the cells by a viral infection. In situations of viral infection, the dsRNA created by viral replication and gene expression binds to the N-terminal domain, activating the protein. PKR activation via dsRNA is length dependent, requiring the dsRNA to be 30 bp in length to bind to PKR molecules. However, excess dsRNA can diminish activation of PKR. Binding to dsRNA is believed to activate PKR by inducing dimerization of the kinase domains and subsequent auto-phosphorylation reactions. PKR can also be activated by the protein PACT via phosphorylation of S287 on its M3 domain. The promoter region of PKR has interferon-stimulated response elements to which Type I interferons (IFN) bind to induce the transcription of PKR genes.
EIF2AK2, also known as PKR, is an interferon-induced, double-stranded RNA-activated serine/threonine-protein kinase that plays a crucial role in the innate immune response to viral infection. It phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha), triggering the integrated stress response (ISR). This phosphorylation converts EIF2S1/eIF-2-alpha into a global protein synthesis inhibitor, shutting down both cellular and viral protein synthesis while promoting the translation of ISR-specific mRNAs, such as ATF4. EIF2AK2's antiviral activity extends to a broad range of DNA and RNA viruses, including HCV, HBV, MV, and HHV-1. Beyond its antiviral role, EIF2AK2 also participates in the regulation of signal transduction, apoptosis, cell proliferation, and differentiation by phosphorylating substrates like p53/TP53, PPP2R5A, DHX9, ILF3, IRS1, and HHV-1 US11. EIF2AK2 possesses tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, promoting its ubiquitination and proteasomal degradation. As an adapter protein or through its kinase activity, EIF2AK2 modulates 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 pro-inflammatory cytokines and IFNs. It activates the NF-kappa-B pathway through interactions with IKBKB and TRAF family proteins, and activates the p38 MAP kinase pathway via interactions with MAP2K6. EIF2AK2 serves as both a positive and negative regulator of the insulin signaling pathway (ISP), inhibiting ISP by phosphorylating IRS1 at 'Ser-312' and promoting ISP through phosphorylation of PPP2R5A, which activates FOXO1, leading to upregulation of IRS2 expression. EIF2AK2 can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2, and NLRC4 inflammasomes. It also plays a role in cytoskeleton regulation by binding to gelsolin (GSN), sequestering it in an inactive conformation away from actin.
EIF2AK2 is also known as DYT33, EIF2AK1, LEUDEN, PKR, PPP1R83, PRKR.
Associated Diseases
- Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome
- Early-onset generalized limb-onset dystonia
- Dystonia 33
