Interferon protein kinase

The molecular basis by which interferons promote their characteristic effects, in particular antiviral activity, is understood at least in part. Interferon stimulation of the JAK-STAT pathway induces synthesis of at least 30 different gene products, many of which cooperate to inhibit viral replication. These antiviral gene products are generally enzymes, the most important of which are 2 -5 oligoadenylate synthetase (2,5-A synthetase) and the eIF-2a protein kinase. 

Exposure of cells to interferon normally results in the induction of a protein kinase termed eIF-2a protein kinase. The enzyme, which is synthesized in a catalytically inactive form, is activated by exposure to dsRNA. The activated kinase then phosplorylates its substrate, i.e. eIF-2a, which is the smallest subunit of initiation factor 2 (eIF2). This, in turn, blocks construction of the smaller ribosomal subunit, thereby preventing translation of all viral (and cellular) mRNA (Figure 8.6). 

Induction of eIF-2a protein kinase is dependent upon both interferon type and cell type. 

PKR, a widely-expressed serine/theonine protein kinase, is activated by dsRNA, interferon, and other agents.48 PKR was first described to inhibit translation via phos-... 

Note that the protein kinase, which phosphorylates the IF-GDP complex is structurally similar to the protein kinase that is activated by double-stranded RNA, i.e. the genome of some viruses. This protein kinase phosphorylates the IF-GDP complex in an infected host cell, so that viral peptide synthesis is inhibited and the virus cannot multiply. Synthesis of this kinase is stimulated by the cytokine, interferon, which is released by virus-infected cells as an early-warning system to adjacent cells not yet infected (Chapter 17 see Figure 17.32). 

Interferons are cellular glycoproteins produced by the host cells which exert complex antiviral, immunoregulatory and antiproliferative activities. After binding to interferon receptors it acts through cellular metabolic processes which involves synthesis of viral RNA and proteins. Interferon receptors are tyrosine protein kinase receptors which on activation phosphorylate cellular proteins. These then induce transcription of interferon induced proteins which exert antiviral effects. There are three type of interferons - alpha, beta and gamma. 

Fig. 1.56. Control of eIF-2 by phosphorylation. Phosphorylated eIF-2 GDP binds strongly to eIF-2B without nucleotide exchange occurring. Initiation of protein biosynthesis is not possible in this case.In reticulocytes, eIF-2 is subject to phosphorylation by the heme-regulated eIF-2-kinase (HRI). The activity of the dimeric HRI is regulated via the heme concentration. Another protein kinase that can phosphorylate and regulate eIF-2 is the RNA-dependent eIF2a-kinase (PKR). The latter is induced by interferons and activated by double stranded RNA.

The receptors for cytokines and interferons are the starting point for signal transduction chains that bring about an activation of transcription factors. The signaling pathway involves the Janus protein kinase and Stat transcription factors (see 11.1.4). Phosphoty-rosine-SH2 interactions are also involved in several steps of signal transduction here. 

Barbieri G, Velazquez L, Scrobogna M, Fellous M, Pellegrini S. Activation of the protein kinase tyk2 by interferon oc/J3. Eur J Biochem 1994 223 427-435. 

This is converted to an inactive phosphorylated form by a dsRNA-dependent protein kinase205 (Fig. 31-10). The protein kinase also appears to be an interferon-induced protein206 as is the oligo(2 -5 A)-activated RNAse indicated in Fig. 31-10.207 Interferons have effects other than inducing the antiviral state. Thus, human IFN-(32 is identical to a B-cell differentiation factor.208 Both IFN-a and IFN-(3 have antigrowth activity and are currently in use for treatment of some forms of cancer as well as for viral infections.209... 

McAllister CS, Samuel CE (2009) The RNA-activated protein kinase enhances the induction of interferon-beta and apoptosis mediated by cytoplasmic RNA sensors. J Biol Chem 284 1644-1651... 

Binding of human interferon-lb to specific cell receptors induces the expression of a number of interferon-induced gene products (e.g., 2, 5 -oligoandenylate synthetase, protein kinase, and indoleamine 2,3-dioxygenase that are believed to be mediators of the biological actions... 

In addition to the examples discussed above, these various reversed-phase HPLC mapping procedures have subsequently found numerous other advocates. Selected recent achievements include application to human hemoglobin variants 9a, 182, 185), the a- and j8-chains of rat hemoglobin 186), polypeptide hormones 9a, 99, 163), porcine C5a anaphylatoxin 187), Aplysia neuroactive polypeptide 188), ACTH/jS-lipotropin precursors 97, 99, 189, 190), oncoproteins 157), chick liver dihydrofolate reductase 191), limulin 192), ATP-citratelyase 193), spore-specific proteins 194), cAMP-dependent protein kinases (/95, 1%), interferons 197), complement components 9a, 198), aj-macroglobulin 198a), lectins 199), phycobiliproteins 200), bovine mitochondrial-F, ATPase 201), collagens, tubulins, and other structural proteins 9a, 202). 

D. M. Rose, B. W. Winston, E. D. Chan, D. W. H. Riches, and P. M. Henson, Interferon-y and Transforming Growth Factor-P Modulate the Activation of Mitogen-Activated Protein Kinases and Tumor Necrosis Factor-a Production Induced by Fcg-Receptor Stimulation in Murine Macrophages, Biochemical Biophysical Research Communication, 238 (1997) 256-260. 

Lechner J and PfallerW. Interferon alpha2b increases paracellular permeability of renal proximal tubular LLC-PKl cells via a mitogen activated protein kinase signaling pathway. Ren Fail 23 573-588,2001. 

Although it is not possible to delineate the mechanisms by which interferon beta-lb exerts its activity in MS. it is known that the interferon binds to specific receptors on cell surfaces and induces the expression of a number of interferon-induced gene products, such as 2. 5 -oligoadenylate synthetase and protein kinase. Additionally, interferon beta-lb blocks the synthesis of INF-y. which is believed to be involved in MS attacks. 

The protein kinase PKR (RNA-specific eIF-2 kinase) is regulated by binding of dsRNA and by interferon on the level of expression. PKR contains two dsRNA binding sites and it is thought that dsRNA binding disrupts inhibitory interactions in PKR leading to its activation. The activation of PKR by dsRNA and its induction by interferon identify PKR as a component of the cellular anit-viral defense. Consistent with this notion, a large number of viruses express inhibitors of PKR. 

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