Genomes and Genes
eif 2 kinase
Summary: A dsRNA-activated cAMP-independent protein serine/threonine kinase that is induced by interferon. In the presence of dsRNA and ATP, the kinase autophosphorylates on several serine and threonine residues. The phosphorylated enzyme catalyzes the phosphorylation of the alpha subunit of EUKARYOTIC INITIATION FACTOR-2, leading to the inhibition of protein synthesis.
- Yusta B, Baggio L, Estall J, Koehler J, Holland D, Li H, et al. GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006;4:391-406 pubmed..These findings demonstrate that GLP-1R signaling directly modulates the ER stress response leading to promotion of beta cell adaptation and survival. ..
- Gilfoy F, Mason P. West Nile virus-induced interferon production is mediated by the double-stranded RNA-dependent protein kinase PKR. J Virol. 2007;81:11148-58 pubmed..Taken together, our data suggest that PKR could serve as a PRR for recognition of WNV infection. ..
- Bergan V, Jagus R, Lauksund S, Kileng Ø, Robertsen B. The Atlantic salmon Z-DNA binding protein kinase phosphorylates translation initiation factor 2 alpha and constitutes a unique orthologue to the mammalian dsRNA-activated protein kinase R. FEBS J. 2008;275:184-97 pubmed..Overall, the results support a role for PKZ, like PKR, in host defense against virus infection. ..
- Nallagatla S, Hwang J, Toroney R, Zheng X, Cameron C, Bevilacqua P. 5'-triphosphate-dependent activation of PKR by RNAs with short stem-loops. Science. 2007;318:1455-8 pubmed..The evidence presented here suggests that this form of RNA-based discrimination may be a critical step in mounting an early immune response. ..
- Sadler A, Williams B. Structure and function of the protein kinase R. Curr Top Microbiol Immunol. 2007;316:253-92 pubmed..Finally, PKR plays a role in normal cell differentiation in platelet-derived growth factor signalling and in osteoblast-mediated calcification. ..
- Garcia M, Meurs E, Esteban M. The dsRNA protein kinase PKR: virus and cell control. Biochimie. 2007;89:799-811 pubmed..As a consequence of the effects of PKR on translation, transcription and apoptosis, PKR can function to control cell growth and cell differentiation, and its activity can be controlled by the action of several oncogenes. ..
- Delgado André N, De Lucca F. Knockdown of PKR expression by RNAi reduces pulmonary metastatic potential of B16-F10 melanoma cells in mice: possible role of NF-kappaB. Cancer Lett. 2007;258:118-25 pubmed..Our results suggest that this effect is mediated by the transcription factor NF-kappaB. This study does not support the concept of PKR as a tumor suppressor. ..
- Eley H, Russell S, Tisdale M. Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase. Br J Cancer. 2007;96:1216-22 pubmed..These results suggest that inhibition of the autophosphorylation of PKR may represent an appropriate target for the attenuation of muscle atrophy in cancer cachexia. ..
- Hamamura K, Liu Y, Yokota H. Microarray analysis of thapsigargin-induced stress to the endoplasmic reticulum of mouse osteoblasts. J Bone Miner Metab. 2008;26:231-40 pubmed publisher..These results support cross-talk between p38 MAPK and ER kinase, presenting a similarity to the responses to hypoxia as well as a pathway toward connective tissue development and organ morphology. ..
- Yan X, Battaglia S, Boucreux D, Chen Z, Brechot C, Pavio N. Mapping of the interacting domains of hepatitis C virus core protein and the double-stranded RNA-activated protein kinase PKR. Virus Res. 2007;125:79-87 pubmed..The precise mapping of core-PKR interaction provides new data to study the molecular mechanism underlying HCV pathogenesis. ..
- Liu L, Wise D, Diehl J, Simon M. Hypoxic reactive oxygen species regulate the integrated stress response and cell survival. J Biol Chem. 2008;283:31153-62 pubmed publisher..Collectively, our data support an important role for ROS in hypoxic cell survival. Under conditions of moderate hypoxia, ROS induce the ISR, thereby promoting energy and redox homeostasis and enhancing cellular survival. ..
- Garcia M, Collado M, Munoz Fontela C, Matheu A, Marcos Villar L, Arroyo J, et al. Antiviral action of the tumor suppressor ARF. EMBO J. 2006;25:4284-92 pubmed..Finally, Arf-null mice were hypersensitive to viral infection compared to wild-type mice. Together, our results reveal a novel and unexpected role for the tumor suppressor ARF in viral infection surveillance. ..
- Nallagatla S, Bevilacqua P. Nucleoside modifications modulate activation of the protein kinase PKR in an RNA structure-specific manner. RNA. 2008;14:1201-13 pubmed publisher..Overall, the findings indicate that nucleoside modifications and wobble pairing may serve to discriminate self-RNA and pathogenic RNA in innate immunity. ..
- Narasimhan J, Joyce B, Naguleswaran A, Smith A, Livingston M, Dixon S, et al. Translation regulation by eukaryotic initiation factor-2 kinases in the development of latent cysts in Toxoplasma gondii. J Biol Chem. 2008;283:16591-601 pubmed publisher..Given its importance to pathogenesis, eIF2 kinase-mediated stress responses may provide opportunities for novel therapeutics. ..
- Perdiguero B, Esteban M. The interferon system and vaccinia virus evasion mechanisms. J Interferon Cytokine Res. 2009;29:581-98 pubmed publisher..The molecular dissection of how VACV prevents the IFN response is providing important insights on our understanding of antiviral action and immune surveillance. ..
- Cohen Chalamish S, Hasson A, Weinberg D, Namer L, Banai Y, Osman F, et al. Dynamic refolding of IFN-gamma mRNA enables it to function as PKR activator and translation template. Nat Chem Biol. 2009;5:896-903 pubmed publisher..This flexibility promotes efficient refolding of interferon-gamma mRNA, which is necessary for its dual function as translation template and activator of PKR, and which thus prevents overexpression of this inflammatory cytokine. ..
- Garaigorta U, Chisari F. Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation. Cell Host Microbe. 2009;6:513-22 pubmed publisher..These results suggest that the ability of HCV to activate PKR may, paradoxically, be advantageous for the virus during an IFN response by preferentially suppressing the translation of ISGs. ..
- Blais J, Addison C, Edge R, Falls T, Zhao H, Wary K, et al. Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress. Mol Cell Biol. 2006;26:9517-32 pubmed
- Sequeira S, Ranganathan A, Adam A, Iglesias B, Farias E, Aguirre Ghiso J. Inhibition of proliferation by PERK regulates mammary acinar morphogenesis and tumor formation. PLoS ONE. 2007;2:e615 pubmed..The possibility that deficiencies in PERK signaling could lead to hyperproliferation of the mammary epithelium and increase the likelihood of tumor formation, is of significance to the understanding of breast cancer. ..
- McKenna S, Lindhout D, Shimoike T, Puglisi J. Biophysical and biochemical investigations of dsRNA-activated kinase PKR. Methods Enzymol. 2007;430:373-96 pubmed..These methods are complemented by nuclear magnetic resonance approaches for probing structural features of PKR activation. Considerations required for both PKR and dsRNA sample preparation are also discussed. ..
- Shang J, Gao N, Kaufman R, Ron D, Harding H, Lehrman M. Translation attenuation by PERK balances ER glycoprotein synthesis with lipid-linked oligosaccharide flux. J Cell Biol. 2007;176:605-16 pubmed..Thus, by sensing ER stress from defective glycosylation, PERK can restore ER homeostasis by balancing polypeptide synthesis with flux through the LLO pathway. ..
- Zhang P, Samuel C. Protein kinase PKR plays a stimulus- and virus-dependent role in apoptotic death and virus multiplication in human cells. J Virol. 2007;81:8192-200 pubmed..Surprisingly, the yield of mutant adenovirus that fails to encode VAI RNA was not enhanced in PKR-deficient cells, indicating the importance of host factors in addition to PKR in conferring the VAI RNA phenotype. ..
- Zhang W, Feng D, Li Y, Iida K, McGrath B, Cavener D. PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab. 2006;4:491-7 pubmed
- Peters G, Li S, Sen G. Phosphorylation of specific serine residues in the PKR activation domain of PACT is essential for its ability to mediate apoptosis. J Biol Chem. 2006;281:35129-36 pubmed..These results indicate that phosphorylation of specific serine residues in the activation domain of PACT is the major mode of transmission of cellular stress response to PKR. ..
- Puthenveetil S, Whitby L, Ren J, Kelnar K, Krebs J, Beal P. Controlling activation of the RNA-dependent protein kinase by siRNAs using site-specific chemical modification. Nucleic Acids Res. 2006;34:4900-11 pubmed..Thus, these studies demonstrate that specific positions in an siRNA can be rationally modified to prevent interaction with components of cellular dsRNA-regulated pathways. ..
- Liu J, HuangFu W, Kumar K, Qian J, Casey J, Hamanaka R, et al. Virus-induced unfolded protein response attenuates antiviral defenses via phosphorylation-dependent degradation of the type I interferon receptor. Cell Host Microbe. 2009;5:72-83 pubmed publisher..These data suggest that specific activation of the PERK component of UPR can favor viral replication. Interfering with PERK-dependent IFNAR1 degradation could therefore contribute to therapeutic strategies against viral infections. ..
- McAllister C, Samuel C. The RNA-activated protein kinase enhances the induction of interferon-beta and apoptosis mediated by cytoplasmic RNA sensors. J Biol Chem. 2009;284:1644-51 pubmed publisher..PKR, in addition to IPS-1 and IRF3 but not TRIF, was required for maximal type I IFN-beta induction and the induction of apoptosis by both transfected PRNAs and polyinosinic-polycytidylic acid. ..
- Wei J, Sheng X, Feng D, McGrath B, Cavener D. PERK is essential for neonatal skeletal development to regulate osteoblast proliferation and differentiation. J Cell Physiol. 2008;217:693-707 pubmed publisher..Taken together, these studies identify PERK as a novel regulator of skeletal development and osteoblast biology. ..
- Dey M, Cao C, Sicheri F, Dever T. Conserved intermolecular salt bridge required for activation of protein kinases PKR, GCN2, and PERK. J Biol Chem. 2007;282:6653-60 pubmed..These results are consistent with the notion that the PKR structure represents the active state of the eIF2alpha kinase domain, whereas the GCN2 structure may represent an inactive state of the kinase. ..
- Wek R, Cavener D. Translational control and the unfolded protein response. Antioxid Redox Signal. 2007;9:2357-71 pubmed
- Rothenburg S, Deigendesch N, Dey M, Dever T, Tazi L. Double-stranded RNA-activated protein kinase PKR of fishes and amphibians: varying the number of double-stranded RNA binding domains and lineage-specific duplications. BMC Biol. 2008;6:12 pubmed..Further implications of our findings for the evolution of the PKR family and for studying PKR/PKZ interactions with viral gene products and their roles in viral infections are discussed...
- Lin J, Li H, Yasumura D, Cohen H, Zhang C, Panning B, et al. IRE1 signaling affects cell fate during the unfolded protein response. Science. 2007;318:944-9 pubmed..Key findings from our studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin in animal models of retinitis pigmentosa. ..
- Lee E, Yoon C, Kim Y, Bae Y. The double-strand RNA-dependent protein kinase PKR plays a significant role in a sustained ER stress-induced apoptosis. FEBS Lett. 2007;581:4325-32 pubmed..These results indicate that the ER-stress-mediated eIF2alpha/ATF4/CHOP/cell death pathway is, to some degree, dependent on PACT-mediated PKR activation apart from the PERK pathway. ..
- Kang J, Kwon S, Park S, Kim Y, Choi S, Kim J, et al. PKR protein kinase is activated by hepatitis C virus and inhibits viral replication through translational control. Virus Res. 2009;142:51-6 pubmed publisher..Together, these results demonstrate that PKR is activated by HCV infection and plays a critical antiviral role through inhibition of viral protein translation. ..
- Unterholzner L, Bowie A. The interplay between viruses and innate immune signaling: recent insights and therapeutic opportunities. Biochem Pharmacol. 2008;75:589-602 pubmed..Further, the viral proteins themselves or derivatives of them may be of use therapeutically to curtail inflammation and autoimmunity. ..
- Dauber B, Schneider J, Wolff T. Double-stranded RNA binding of influenza B virus nonstructural NS1 protein inhibits protein kinase R but is not essential to antagonize production of alpha/beta interferon. J Virol. 2006;80:11667-77 pubmed..Thus, our findings indicate an unexpected mechanistic dichotomy of the influenza B virus NS1 protein in the suppression of antiviral responses, which involves at least one activity that is largely separable from dsRNA binding. ..
- Fennell C, Babbitt S, Russo I, Wilkes J, Ranford Cartwright L, Goldberg D, et al. PfeIK1, a eukaryotic initiation factor 2alpha kinase of the human malaria parasite Plasmodium falciparum, regulates stress-response to amino-acid starvation. Malar J. 2009;8:99 pubmed publisher..falciparum. ..
- Yang X, Chan C. Repression of PKR mediates palmitate-induced apoptosis in HepG2 cells through regulation of Bcl-2. Cell Res. 2009;19:469-86 pubmed publisher..In summary, PKR mediates the regulation of the protein level and the phosphorylation status of Bcl-2, providing a novel mechanism of palmitate-induced apoptosis in HepG2 cells. ..
- Tesfay M, Yin J, Gardner C, Khoretonenko M, Korneeva N, Rhoads R, et al. Alpha/beta interferon inhibits cap-dependent translation of viral but not cellular mRNA by a PKR-independent mechanism. J Virol. 2008;82:2620-30 pubmed
- Feng Z, Cerveny M, Yan Z, He B. The VP35 protein of Ebola virus inhibits the antiviral effect mediated by double-stranded RNA-dependent protein kinase PKR. J Virol. 2007;81:182-92 pubmed..Together, these results show that the VP35 protein targets multiple pathways of the interferon system. ..
- Seo E, Liu F, Kawagishi Kobayashi M, Ung T, Cao C, Dar A, et al. Protein kinase PKR mutants resistant to the poxvirus pseudosubstrate K3L protein. Proc Natl Acad Sci U S A. 2008;105:16894-9 pubmed publisher..We propose that these paradoxical effects of the PKR mutations on pseudosubstrate vs. substrate interactions reflect differences between the rigid K3L protein and the plastic nature of eIF2alpha around the Ser-51 phosphorylation site...
- Daher A, Laraki G, Singh M, Melendez Peña C, Bannwarth S, Peters A, et al. TRBP control of PACT-induced phosphorylation of protein kinase R is reversed by stress. Mol Cell Biol. 2009;29:254-65 pubmed publisher..Our results demonstrate that in cells, TRBP controls PACT activation of PKR, an activity that is reversed by stress. ..
- Ito M, Onuki R, Bando Y, Tohyama M, Sugiyama Y. Phosphorylated PKR contributes the induction of GRP94 under ER stress. Biochem Biophys Res Commun. 2007;360:615-20 pubmed..These results suggest that a novel mechanism other than ERSE-dependent mRNA transcription is required for the induction of GRP94 and phosphorylation of PKR contributes to the induction of GRP94 under ER stress. ..
- Kang M, Lee C, Lee J, Dela Cruz C, Chen Z, Enelow R, et al. Cigarette smoke selectively enhances viral PAMP- and virus-induced pulmonary innate immune and remodeling responses in mice. J Clin Invest. 2008;118:2771-84 pubmed publisher..These studies demonstrate that CS selectively augments the airway and alveolar inflammatory and remodeling responses induced in the murine lung by viral PAMPs and viruses. ..
- Kazemi S, Mounir Z, Baltzis D, Raven J, Wang S, Krishnamoorthy J, et al. A novel function of eIF2alpha kinases as inducers of the phosphoinositide-3 kinase signaling pathway. Mol Biol Cell. 2007;18:3635-44 pubmed..Our data reveal a novel property of eIF2alpha kinases as activators of PI3K signaling and cell survival. ..
- Shimoike T, McKenna S, Lindhout D, Puglisi J. Translational insensitivity to potent activation of PKR by HCV IRES RNA. Antiviral Res. 2009;83:228-37 pubmed publisher..Thus, HCV can use structured RNAs to its advantage in translation, while avoiding the deleterious effects of PKR activation. ..
- McKenna S, Lindhout D, Shimoike T, Aitken C, Puglisi J. Viral dsRNA inhibitors prevent self-association and autophosphorylation of PKR. J Mol Biol. 2007;372:103-13 pubmed..These data indicate that inhibitory dsRNAs bind preferentially to the latent, dephosphorylated form of PKR and prevent dimerization that is required for trans-autophosphorylation. ..