Protein kinase R

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Protein kinase RNA-activated 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.[1][2]

PKR protects against viral infections.

Mechanism of action

Protein kinase-R is activated by double-stranded RNA (dsRNA), introduced to the cells by a viral infection. PKR can also be activated by the protein PACT or by heparin. PKR contains an N-terminal dsRNA binding domain (dsRBD) and a C-terminal kinase domain, that gives it pro-apoptotic (cell-killing) functions. The dsRBD consists of two tandem copies of a conserved double stranded RNA binding motif, dsRBM1 and dsRBM2. PKR is induced by interferon in a latent state. Binding to dsRNA is believed to activate PKR by inducing dimerization and subsequent auto-phosphorylation reactions. In situations of viral infection, the dsRNA created by viral replication and gene expression binds to the N-terminal domain, activating the protein. Once active, PKR is able to phosphorylate the eukaryotic translation initiation factor eIF2α. This inhibits further cellular mRNA translation, thereby preventing viral protein synthesis. Since ElF2α is involved in the commonly initiation translation from an AUG codon, the alternative non-AUG initiation takes place instead. An example of mRNAs using non-AUG initiation are mRNAs for the heat shock proteins. Active PKR is also able to mediate the activation of the transcription factor NFkB, by phosphorylating its inhibitory subunit, IkB. Activated NFkB upregulates the expression of Interferon cytokines, which work to spread the antiviral signal locally. Active PKR is also able to activate tumor suppressor PP2A which regulates the cell cycle and the metabolism. Through complex mechanisms, active PKR is also able to induce cellular apoptosis, to prevent further viral spread.

PKR stress pathway

PKR is in the center of cellular response to different stress signals such as pathogens, lack of nutrients, cytokines, irradiation, mechanical stress, or ER stress. PKR pathway leads to stress response through activation of other stress pathway such as JNK, p38, NFkB, PP2A and phosphorylation of eIF2α. ER stress caused by excess of unfolded proteins leads to inflammatory responses. PKR contributes to this response by interacting with several inflammatory kinases such as IKK, JNK, ElF2α, insulin receptor and others. This metabolically activated inflammatory complex is called metabolic inflammasome or metaflammasome.[3][4]

Viral defense

Viruses have developed many mechanisms to counteract the PKR mechanism. It may be done by Decoy dsRNA, degradation, hiding of virus dsRNA, dimerization block, dephosphorylation of substrate or by a pseudosubstrate.

For instance, Epstein-Barr Virus (EBV) uses the gene EBER-1 to produce decoy dsRNA. This leads to cancers such as Burkitt's lymphoma, Hodgkin's Disease, nasopharyngeal carcinoma and various leukemias.

Viral defence mechanisms against PKR
Defence type Virus Molecule
Decoy dsRNA Adenovirus VAI RNA
Epstein-Barr virus EBER
HIV TAR
PKR degradation Poliovirus 2Apro
hide viral dsRNA Vaccinia virus E3L
Reovirus σ3
Influenza virus NS1
Dimerization block Influenza virus p58IPK
Hepatitis C virus NS5A
Pseudosubstrate Vaccinia virus K3L
HIV Tat
Dephosphorylation of substrate Herpes simplex virus ICP34.5

Memory and learning

PKR knockout mice or inhibition of PKR in mice enhances memory and learning.[5]

Neuronal degeneration disease

First report in 2002 has been shown that immunohistochemical marker for phosphorylated PKR and eIF2α was displayed positively in degenerating neurons in the hippocampus and the frontal cortex of patients with Alzheimer's Disease (AD), suggesting the link between PKR and AD. Additionally, many of these neurons were also immunostained with an antibody for phosphorylated Tau protein.[6] Activated PKR was specifically found in the cytoplasm and nucleus, as well as co-localized with neuronal apoptotic markers.[7] Further studies have assessed the levels of PKR in blood and cerebrospinal fluid (CSF) of AD patients and controls. The result of an analysis of the concentrations of total and phosphorylated PKR (pPKR) in peripheral blood mononuclear cells (PBMCs) in 23 AD patients and 19 control individuals showed statistically significant increased levels of the ratio of PKR/ phosphorylated PKR in AD patients compared with controls.[8] Assessments of CSF biomarkers, such as Aβ1-42, Aβ1-40, Tau, and phosphorylated Tau at threonine 181, have been a validated use in clinical research and in routine practice to determine whether patients have CSF abnormalities and AD brain lesions. A study found that "total PKR and pPKR concentrations were elevated in AD and amnestic mild cognitive impairment subjects with a pPKR value (optical density units) discriminating AD patients from control subjects with a sensitivity of 91.1% and a specificity of 94.3%. Among AD patients, total PKR and pPKR levels correlate with CSF p181tau levels. Some AD patients with normal CSF Aß, T-tau, or p181tau levels had abnormal total PKR and pPKR levels".[9] It was concluded that the PKR-eIF2α pro-apoptotic pathway could be involved in neuronal degeneration that leads to various neuropathological lesions as a function of neuronal susceptibility.

PKR and beta amyloid

Activation of PKR can cause accumulation of amyloid β-peptide (Aβ) via de-repression of BACE1 (ß-site APP Cleaving Enzyme) expression in Alzheimer Disease patients.[10] Normally, the 5′untranslated region (5′UTR) in the BACE1 promoter would fundamentally inhibit the expression of BACE1 gene. However, BACE1 expression can be activated by phosphorylation of eIF2a, which reverses the inhibitory effect exerted by BACE1 5′UTR. Phosphorylation of eIF2a is triggered by activation of PKR. Viral infection such as Herpes Simplex Virus (HSV) or oxidative stress can both increase BACE1 expression through activation of PKR-eIF2a pathway.[11]

In addition, the increased activity of BACE1 could also lead to β-cleaved carboxy-terminal fragment of β-Amyloid precursor protein (APP-βCTF) induced dysfunction of endosomes in AD.[12] Endosomes are highly active β-Amyloid precursor protein (APP) processing sites, and endosome abnormalities are associated with upregulated expression of early endosomal regulator, rab5. These are the earliest known disease-specific neuronal response in AD. Increased activity of BACE1 leads to synthesis of the APP-βCTF. An elevated level of βCTF then causes rab 5 overactivation. βCTF recruits APPL1 to rab5 endosomes, where it stabilizes active GTP-rab5, leading to pathologically accelerated endocytosis, endosome swelling and selectively impaired axonal transport of rab5 endosomes.

PKR and Tau phosphorylation

It is reported earlier that phosphorylated PKR could co-localize with phosphorylated Tau protein in affected neurons.[13][6] A protein phosphatase-2A inhibitor (PP2A inhibitor) – Okadaic acid (OA) – is known to increase tau phosphorylation, Aβ deposition and neuronal death. It is studied that OA also induces PKR phosphorylation and thus, eIF2a phosphorylation. eIF2a phosphorylation then induces activation of transcription factor 4 (ATF4), which induces apoptosis and nuclear translocation, contributing to neuronal death.[14]

Glycogen Synthase Kinase Aβ (GSK-3β) is responsible for tau phosphorylation and controls several cellular functions including apoptosis. Another study demonstrated that tunicamycin or Aβ treatment can induce PKR activation in human neuroblastoma cells and can trigger GSK3β activation, as well as tau phosphorylation. They found that in AD brains, both activated PKR and GSK3β co-localize with phosphorylated tau in neurons. In SH-SY5Y cell cultures, tunicamycin and Aβ(1-42) activate PKR, which then can modulate GSK-3β activation and induce tau phosphorylation, apoptosis. All these processes are attenuated by PKR inhibitors or PKR siRNA. PKR could represent a crucial signaling point relaying stress signals to neuronal pathways by interacting with transcription factor or indirectly controlling GSK3β activation, leading to cellular degeneration in AD.[15]

Fetal alcohol syndrome

PKR also mediates ethanol-induced protein synthesis inhibition and apoptosis which is linked to fetal alcohol syndrome.[16]

Interactions

Protein kinase R has been shown to interact with:

References

  1. ↑ "Entrez Gene: EIF2AK2 eukaryotic translation initiation factor 2-alpha kinase 2".
  2. ↑ Feng GS, Chong K, Kumar A, Williams BR (June 1992). "Identification of double-stranded RNA-binding domains in the interferon-induced double-stranded RNA-activated p68 kinase". Proceedings of the National Academy of Sciences of the United States of America. 89 (12): 5447–51. doi:10.1073/pnas.89.12.5447. PMC 49309. PMID 1351683.
  3. ↑ García MA, Gil J, Ventoso I, Guerra S, Domingo E, Rivas C, Esteban M (December 2006). "Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action". Microbiology and Molecular Biology Reviews. 70 (4): 1032–60. doi:10.1128/MMBR.00027-06. PMC 1698511. PMID 17158706.
  4. ↑ Hotamisligil GS (March 2010). "Endoplasmic reticulum stress and the inflammatory basis of metabolic disease". Cell. 140 (6): 900–17. doi:10.1016/j.cell.2010.02.034. PMC 2887297. PMID 20303879.
  5. ↑ Zhu PJ, Huang W, Kalikulov D, Yoo JW, Placzek AN, Stoica L, Zhou H, Bell JC, Friedlander MJ, Krnjević K, Noebels JL, Costa-Mattioli M (December 2011). "Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition". Cell. 147 (6): 1384–96. doi:10.1016/j.cell.2011.11.029. PMC 3569515. PMID 22153080. Lay summary – canada.com.
  6. ↑ 6.0 6.1 Chang RC, Wong AK, Ng HK, Hugon J (December 2002). "Phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) is associated with neuronal degeneration in Alzheimer's disease". NeuroReport. 13 (18): 2429–32. doi:10.1097/01.wnr.0000048020.74602.bb. PMID 12499843.
  7. ↑ Page G, Rioux Bilan A, Ingrand S, Lafay-Chebassier C, Pain S, Perault Pochat MC, Bouras C, Bayer T, Hugon J (2006). "Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer's disease". Neuroscience. 139 (4): 1343–54. doi:10.1016/j.neuroscience.2006.01.047. PMID 16581193.
  8. ↑ Paccalin M, Pain-Barc S, Pluchon C, Paul C, Besson MN, Carret-Rebillat AS, Rioux-Bilan A, Gil R, Hugon J (2006). "Activated mTOR and PKR kinases in lymphocytes correlate with memory and cognitive decline in Alzheimer's disease". Dementia and Geriatric Cognitive Disorders. 22 (4): 320–6. doi:10.1159/000095562. PMID 16954686.
  9. ↑ Mouton-Liger F, Paquet C, Dumurgier J, Lapalus P, Gray F, Laplanche JL, Hugon J (May 2012). "Increased cerebrospinal fluid levels of double-stranded RNA-dependant protein kinase in Alzheimer's disease". Biological Psychiatry. 71 (9): 829–35. doi:10.1016/j.biopsych.2011.11.031. PMID 22281122.
  10. ↑ Ill-Raga G, Palomer E, Wozniak MA, Ramos-Fernández E, Bosch-Morató M, Tajes M, Guix FX, Galán JJ, Clarimón J, Antúnez C, Real LM, Boada M, Itzhaki RF, Fandos C, Muñoz FJ (2011-06-28). "Activation of PKR causes amyloid ß-peptide accumulation via de-repression of BACE1 expression". PLOS One. 6 (6): e21456. doi:10.1371/journal.pone.0021456. PMC 3125189. PMID 21738672.
  11. ↑ Mouton-Liger F, Paquet C, Dumurgier J, Bouras C, Pradier L, Gray F, Hugon J (June 2012). "Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway". Biochimica et Biophysica Acta. 1822 (6): 885–96. doi:10.1016/j.bbadis.2012.01.009. PMID 22306812.
  12. ↑ Kim S, Sato Y, Mohan PS, Peterhoff C, Pensalfini A, Rigoglioso A, Jiang Y, Nixon RA (May 2016). "Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease". Molecular Psychiatry. 21 (5): 707–16. doi:10.1038/mp.2015.97. PMC 4721948. PMID 26194181.
  13. ↑ Peel AL, Bredesen DE (October 2003). "Activation of the cell stress kinase PKR in Alzheimer's disease and human amyloid precursor protein transgenic mice". Neurobiology of Disease. 14 (1): 52–62. PMID 13678666.
  14. ↑ Kim SM, Yoon SY, Choi JE, Park JS, Choi JM, Nguyen T, Kim DH (September 2010). "Activation of eukaryotic initiation factor-2 α-kinases in okadaic acid-treated neurons". Neuroscience. 169 (4): 1831–9. doi:10.1016/j.neuroscience.2010.06.016. PMID 20600673.
  15. ↑ Bose A, Mouton-Liger F, Paquet C, Mazot P, Vigny M, Gray F, Hugon J (March 2011). "Modulation of tau phosphorylation by the kinase PKR: implications in Alzheimer's disease". Brain Pathology. 21 (2): 189–200. doi:10.1111/j.1750-3639.2010.00437.x. PMID 21029237.
  16. ↑ Chen G, Ma C, Bower KA, Ke Z, Luo J (June 2006). "Interaction between RAX and PKR modulates the effect of ethanol on protein synthesis and survival of neurons". The Journal of Biological Chemistry. 281 (23): 15909–15. doi:10.1074/jbc.M600612200. PMID 16574643.
  17. ↑ Takizawa T, Tatematsu C, Nakanishi Y (December 2002). "Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1. Implications for apoptosis signaling pathways". European Journal of Biochemistry. 269 (24): 6126–32. doi:10.1046/j.1432-1033.2002.03325.x. PMID 12473108.
  18. ↑ 18.0 18.1 Polyak SJ, Tang N, Wambach M, Barber GN, Katze MG (January 1996). "The P58 cellular inhibitor complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity". The Journal of Biological Chemistry. 271 (3): 1702–7. doi:10.1074/jbc.271.3.1702. PMID 8576172.
  19. ↑ Saunders LR, Perkins DJ, Balachandran S, Michaels R, Ford R, Mayeda A, Barber GN (August 2001). "Characterization of two evolutionarily conserved, alternatively spliced nuclear phosphoproteins, NFAR-1 and -2, that function in mRNA processing and interact with the double-stranded RNA-dependent protein kinase, PKR". The Journal of Biological Chemistry. 276 (34): 32300–12. doi:10.1074/jbc.M104207200. PMID 11438536.
  20. ↑ Langland JO, Kao PN, Jacobs BL (May 1999). "Nuclear factor-90 of activated T-cells: A double-stranded RNA-binding protein and substrate for the double-stranded RNA-dependent protein kinase, PKR". Biochemistry. 38 (19): 6361–8. doi:10.1021/bi982410u. PMID 10320367.
  21. ↑ Parker LM, Fierro-Monti I, Mathews MB (August 2001). "Nuclear factor 90 is a substrate and regulator of the eukaryotic initiation factor 2 kinase double-stranded RNA-activated protein kinase". The Journal of Biological Chemistry. 276 (35): 32522–30. doi:10.1074/jbc.M104408200. PMID 11438540.
  22. ↑ Patel RC, Vestal DJ, Xu Z, Bandyopadhyay S, Guo W, Erme SM, Williams BR, Sen GC (July 1999). "DRBP76, a double-stranded RNA-binding nuclear protein, is phosphorylated by the interferon-induced protein kinase, PKR". The Journal of Biological Chemistry. 274 (29): 20432–7. doi:10.1074/jbc.274.29.20432. PMID 10400669.
  23. ↑ Gil J, Esteban M, Roth D (December 2000). "In vivo regulation of the dsRNA-dependent protein kinase PKR by the cellular glycoprotein p67". Biochemistry. 39 (51): 16016–25. doi:10.1021/bi001754t. PMID 11123929.
  24. ↑ Cuddihy AR, Wong AH, Tam NW, Li S, Koromilas AE (April 1999). "The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro". Oncogene. 18 (17): 2690–702. doi:10.1038/sj.onc.1202620. PMID 10348343.
  25. ↑ Tan SL, Tareen SU, Melville MW, Blakely CM, Katze MG (September 2002). "The direct binding of the catalytic subunit of protein phosphatase 1 to the PKR protein kinase is necessary but not sufficient for inactivation and disruption of enzyme dimer formation". The Journal of Biological Chemistry. 277 (39): 36109–17. doi:10.1074/jbc.M205109200. PMID 12138106.
  26. ↑ Huang X, Hutchins B, Patel RC (August 2002). "The C-terminal, third conserved motif of the protein activator PACT plays an essential role in the activation of double-stranded-RNA-dependent protein kinase (PKR)". The Biochemical Journal. 366 (Pt 1): 175–86. doi:10.1042/BJ20020204. PMC 1222748. PMID 11985496.
  27. ↑ Patel RC, Sen GC (August 1998). "PACT, a protein activator of the interferon-induced protein kinase, PKR". The EMBO Journal. 17 (15): 4379–90. doi:10.1093/emboj/17.15.4379. PMC 1170771. PMID 9687506.
  28. ↑ Wong AH, Tam NW, Yang YL, Cuddihy AR, Li S, Kirchhoff S, Hauser H, Decker T, Koromilas AE (March 1997). "Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways". The EMBO Journal. 16 (6): 1291–304. doi:10.1093/emboj/16.6.1291. PMC 1169727. PMID 9135145.
  29. ↑ Wong AH, Durbin JE, Li S, Dever TE, Decker T, Koromilas AE (April 2001). "Enhanced antiviral and antiproliferative properties of a STAT1 mutant unable to interact with the protein kinase PKR". The Journal of Biological Chemistry. 276 (17): 13727–37. doi:10.1074/jbc.M011240200. PMID 11278865.
  30. ↑ Cosentino GP, Venkatesan S, Serluca FC, Green SR, Mathews MB, Sonenberg N (October 1995). "Double-stranded-RNA-dependent protein kinase and TAR RNA-binding protein form homo- and heterodimers in vivo". Proceedings of the National Academy of Sciences of the United States of America. 92 (21): 9445–9. doi:10.1073/pnas.92.21.9445. PMC 40818. PMID 7568151.
  31. ↑ Daher A, Longuet M, Dorin D, Bois F, Segeral E, Bannwarth S, Battisti PL, Purcell DF, Benarous R, Vaquero C, Meurs EF, Gatignol A (September 2001). "Two dimerization domains in the trans-activation response RNA-binding protein (TRBP) individually reverse the protein kinase R inhibition of HIV-1 long terminal repeat expression". The Journal of Biological Chemistry. 276 (36): 33899–905. doi:10.1074/jbc.M103584200. PMID 11438532.

Further reading

  • Williams BR (November 1999). "PKR; a sentinel kinase for cellular stress". Oncogene. 18 (45): 6112–20. doi:10.1038/sj.onc.1203127. PMID 10557102.
  • García MA, Meurs EF, Esteban M (2007). "The dsRNA protein kinase PKR: virus and cell control". Biochimie. 89 (6–7): 799–811. doi:10.1016/j.biochi.2007.03.001. PMID 17451862.
  • Thomis DC, Doohan JP, Samuel CE (May 1992). "Mechanism of interferon action: cDNA structure, expression, and regulation of the interferon-induced, RNA-dependent P1/eIF-2 alpha protein kinase from human cells". Virology. 188 (1): 33–46. doi:10.1016/0042-6822(92)90732-5. PMID 1373553.
  • McCormack SJ, Thomis DC, Samuel CE (May 1992). "Mechanism of interferon action: identification of a RNA binding domain within the N-terminal region of the human RNA-dependent P1/eIF-2 alpha protein kinase". Virology. 188 (1): 47–56. doi:10.1016/0042-6822(92)90733-6. PMID 1373554.
  • Mellor H, Proud CG (July 1991). "A synthetic peptide substrate for initiation factor-2 kinases". Biochemical and Biophysical Research Communications. 178 (2): 430–7. doi:10.1016/0006-291X(91)90125-Q. PMID 1677563.
  • Meurs E, Chong K, Galabru J, Thomas NS, Kerr IM, Williams BR, Hovanessian AG (July 1990). "Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon". Cell. 62 (2): 379–90. doi:10.1016/0092-8674(90)90374-N. PMID 1695551.
  • Silverman RH, Sengupta DN (1991). "Translational regulation by HIV leader RNA, TAT, and interferon-inducible enzymes". Journal of Experimental Pathology. 5 (2): 69–77. PMID 1708818.
  • Roy S, Katze MG, Parkin NT, Edery I, Hovanessian AG, Sonenberg N (March 1990). "Control of the interferon-induced 68-kilodalton protein kinase by the HIV-1 tat gene product". Science. 247 (4947): 1216–9. doi:10.1126/science.2180064. PMID 2180064.
  • McMillan NA, Chun RF, Siderovski DP, Galabru J, Toone WM, Samuel CE, Mak TW, Hovanessian AG, Jeang KT, Williams BR (November 1995). "HIV-1 Tat directly interacts with the interferon-induced, double-stranded RNA-dependent kinase, PKR". Virology. 213 (2): 413–24. doi:10.1006/viro.1995.0014. PMID 7491766.
  • Barber GN, Edelhoff S, Katze MG, Disteche CM (June 1993). "Chromosomal assignment of the interferon-inducible double-stranded RNA-dependent protein kinase (PRKR) to human chromosome 2p21-p22 and mouse chromosome 17 E2". Genomics. 16 (3): 765–7. doi:10.1006/geno.1993.1262. PMID 7686883.
  • Squire J, Meurs EF, Chong KL, McMillan NA, Hovanessian AG, Williams BR (June 1993). "Localization of the human interferon-induced, ds-RNA activated p68 kinase gene (PRKR) to chromosome 2p21-p22". Genomics. 16 (3): 768–70. doi:10.1006/geno.1993.1263. PMID 7686884.
  • Prigmore E, Ahmed S, Best A, Kozma R, Manser E, Segal AW, Lim L (May 1995). "A 68-kDa kinase and NADPH oxidase component p67phox are targets for Cdc42Hs and Rac1 in neutrophils". The Journal of Biological Chemistry. 270 (18): 10717–22. doi:10.1074/jbc.270.18.10717. PMID 7738010.
  • Barber GN, Wambach M, Wong ML, Dever TE, Hinnebusch AG, Katze MG (May 1993). "Translational regulation by the interferon-induced double-stranded-RNA-activated 68-kDa protein kinase". Proceedings of the National Academy of Sciences of the United States of America. 90 (10): 4621–5. doi:10.1073/pnas.90.10.4621. PMC 46564. PMID 8099444.
  • Chen ZJ, Parent L, Maniatis T (March 1996). "Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity". Cell. 84 (6): 853–62. doi:10.1016/S0092-8674(00)81064-8. PMID 8601309.
  • Kuhen KL, Shen X, Carlisle ER, Richardson AL, Weier HU, Tanaka H, Samuel CE (August 1996). "Structural organization of the human gene (PKR) encoding an interferon-inducible RNA-dependent protein kinase (PKR) and differences from its mouse homolog". Genomics. 36 (1): 197–201. doi:10.1006/geno.1996.0446. PMID 8812437.
  • Taylor DR, Lee SB, Romano PR, Marshak DR, Hinnebusch AG, Esteban M, Mathews MB (November 1996). "Autophosphorylation sites participate in the activation of the double-stranded-RNA-activated protein kinase PKR". Molecular and Cellular Biology. 16 (11): 6295–302. PMC 231632. PMID 8887659.
  • Kuhen KL, Shen X, Samuel CE (October 1996). "Mechanism of interferon action sequence of the human interferon-inducible RNA-dependent protein kinase (PKR) deduced from genomic clones". Gene. 178 (1–2): 191–3. doi:10.1016/0378-1119(96)00314-9. PMID 8921913.
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