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PMID: 21145228 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Regulation of innate immunity through RNA structure and the protein kinase PKR.

Current opinion in structural biology ·Vol. 21 ·No. 1 ·2011-02-00 ·Pages 119-27

Nallagatla SR, Toroney R, Bevilacqua PC

Abstract

Molecular recognition of RNA structure is key to innate immunity. The protein kinase PKR differentiates self from non-self by recognition of molecular patterns in RNA. Certain biological RNAs induce autophosphorylation of PKR, activating it to phosphorylate eukaryotic initiation factor 2α (eIF2α), which leads to inhibition of translation. Additional biological RNAs inhibit PKR, while still others have no effect. The aim of this article is to develop a cohesive framework for understanding and predicting PKR function in the context of diverse RNA structure. We present effects of recently characterized viral and cellular RNAs on regulation of PKR, as well as siRNAs. A central conclusion is that assembly of accessible long double-stranded RNA (dsRNA) elements within biological RNAs plays a key role in regulation of PKR kinase. Strategies for forming such elements include RNA dimerization, formation of symmetrical helical defects, A-form dsRNA mimicry, and coaxial stacking of helices.

MeSH Terms
Animals Enzyme Activation Humans Immunity, Innate Nucleic Acid Conformation RNA/chemistry,metabolism eIF-2 Kinase/metabolism
Chemicals
RNA eIF-2 Kinase
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Nallagatla Subba Rao
Department of Chemistry, The Pennsylvania State University, 104 Chemistry Bldg, University Park, PA 16802, USA.
Toroney Rebecca
Bevilacqua Philip C
References (62)
62 references, click to expand
  1. Mechanism of PKR activation: dimerization and kinase activation in the absence of double-stranded RNA.
    J Mol Biol. 2005 Jan 7;345(1):81-90 PMID: 15567412
  2. Regulation of PKR by HCV IRES RNA: importance of domain II and NS5A.
    J Mol Biol. 2010 Jul 16;400(3):393-412 PMID: 20447405
  3. PKR, a p53 target gene, plays a crucial role in the tumor-suppressor function of p53.
    Proc Natl Acad Sci U S A. 2009 May 12;106(19):7852-7 PMID: 19416861
  4. Role of the trans-activation response element in dimerization of HIV-1 RNA.
    J Biol Chem. 2004 May 21;279(21):22243-9 PMID: 15014074
  5. The 3'-untranslated regions of cytoskeletal muscle mRNAs inhibit translation by activating the double-stranded RNA-dependent protein kinase PKR.
    Nucleic Acids Res. 2002 Mar 1;30(5):1205-12 PMID: 11861913
  6. RNA 1997-2007: a remarkable decade of discovery.
    Mol Cell. 2007 Dec 14;28(5):715-20 PMID: 18082596
  7. Tyrosine phosphorylation acts as a molecular switch to full-scale activation of the eIF2alpha RNA-dependent protein kinase.
    Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):63-8 PMID: 16373505
  8. Analysis of PKR activation using analytical ultracentrifugation.
    Macromol Biosci. 2010 Jul 7;10(7):703-13 PMID: 20533534
  9. Analysis of adenovirus VA RNAI structure and stability using compensatory base pair modifications.
    Nucleic Acids Res. 2008 Mar;36(5):1645-53 PMID: 18250084
  10. Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA.
    RNA. 2003 Jul;9(7):858-70 PMID: 12810919
  11. The PKR-binding domain of adenovirus VA RNAI exists as a mixture of two functionally non-equivalent structures.
    Nucleic Acids Res. 2009 Sep;37(17):5830-7 PMID: 19635730
  12. Innate sensing of self and non-self RNAs by Toll-like receptors.
    Trends Mol Med. 2006 Apr;12(4):167-76 PMID: 16530484
  13. Controlling activation of the RNA-dependent protein kinase by siRNAs using site-specific chemical modification.
    Nucleic Acids Res. 2006;34(17):4900-11 PMID: 16982647
  14. The interplay between viruses and innate immune signaling: recent insights and therapeutic opportunities.
    Biochem Pharmacol. 2008 Feb 1;75(3):589-602 PMID: 17868652
  15. How RNA folds.
    J Mol Biol. 1999 Oct 22;293(2):271-81 PMID: 10550208
  16. Nucleotide sequences and modifications that determine RIG-I/RNA binding and signaling activities.
    J Virol. 2009 May;83(9):4174-84 PMID: 19224987
  17. The double-stranded-RNA-binding motif: interference and much more.
    Nat Rev Mol Cell Biol. 2004 Dec;5(12):1013-23 PMID: 15573138
  18. RNA recognition by a Staufen double-stranded RNA-binding domain.
    EMBO J. 2000 Mar 1;19(5):997-1009 PMID: 10698941
  19. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis.
    Cell. 2010 Feb 5;140(3):338-48 PMID: 20144759
  20. Magnesium-dependent interaction of PKR with adenovirus VAI.
    J Mol Biol. 2010 Oct 1;402(4):638-44 PMID: 20713064
  21. Viral dsRNA inhibitors prevent self-association and autophosphorylation of PKR.
    J Mol Biol. 2007 Sep 7;372(1):103-13 PMID: 17619024
  22. The solution structure of the ADAR2 dsRBM-RNA complex reveals a sequence-specific readout of the minor groove.
    Cell. 2010 Oct 15;143(2):225-37 PMID: 20946981
  23. Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action.
    Microbiol Mol Biol Rev. 2006 Dec;70(4):1032-60 PMID: 17158706
  24. Nucleoside modifications modulate activation of the protein kinase PKR in an RNA structure-specific manner.
    RNA. 2008 Jun;14(6):1201-13 PMID: 18426922
  25. Dynamic refolding of IFN-gamma mRNA enables it to function as PKR activator and translation template.
    Nat Chem Biol. 2009 Dec;5(12):896-903 PMID: 19801993
  26. A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells.
    Nat Biotechnol. 2006 May;24(5):559-65 PMID: 16648842
  27. Adenosine deaminase ADAR1 increases gene expression at the translational level by decreasing protein kinase PKR-dependent eIF-2alpha phosphorylation.
    J Mol Biol. 2009 Nov 6;393(4):777-87 PMID: 19733181
  28. A cis-acting element in the 3'-untranslated region of human TNF-alpha mRNA renders splicing dependent on the activation of protein kinase PKR.
    Genes Dev. 1999 Dec 15;13(24):3280-93 PMID: 10617576
  29. PKR and the ribosome compete for mRNA.
    Nat Chem Biol. 2009 Dec;5(12):873-4 PMID: 19915532
  30. 5'-triphosphate-dependent activation of PKR by RNAs with short stem-loops.
    Science. 2007 Nov 30;318(5855):1455-8 PMID: 18048689
  31. Small interfering RNAs induce macrophage migration inhibitory factor production and proliferation in breast cancer cells via a double-stranded RNA-dependent protein kinase-dependent mechanism.
    J Immunol. 2008 Jun 1;180(11):7125-33 PMID: 18490711
  32. Compact intermediates in RNA folding.
    Annu Rev Biophys. 2010;39:61-77 PMID: 20192764
  33. RNA dimerization promotes PKR dimerization and activation.
    J Mol Biol. 2009 Jul 10;390(2):319-38 PMID: 19445956
  34. Structural basis for recognition of the AGNN tetraloop RNA fold by the double-stranded RNA-binding domain of Rnt1p RNase III.
    Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8307-12 PMID: 15150409
  35. Molecular basis of double-stranded RNA-protein interactions: structure of a dsRNA-binding domain complexed with dsRNA.
    EMBO J. 1998 Dec 15;17(24):7505-13 PMID: 9857205
  36. Human interferon-gamma mRNA autoregulates its translation through a pseudoknot that activates the interferon-inducible protein kinase PKR.
    Cell. 2002 Jan 25;108(2):221-32 PMID: 11832212
  37. Structure of HCV IRES domain II determined by NMR.
    Nat Struct Biol. 2003 Dec;10(12):1033-8 PMID: 14578934
  38. Naturally occurring nucleoside modifications suppress the immunostimulatory activity of RNA: implication for therapeutic RNA development.
    Curr Opin Drug Discov Devel. 2007 Sep;10(5):523-32 PMID: 17786850
  39. Analysis of PKR structure by small-angle scattering.
    J Mol Biol. 2009 Apr 10;387(4):910-20 PMID: 19232355
  40. Influenza B virus ribonucleoprotein is a potent activator of the antiviral kinase PKR.
    PLoS Pathog. 2009 Jun;5(6):e1000473 PMID: 19521506
  41. Pathogen recognition and innate immunity.
    Cell. 2006 Feb 24;124(4):783-801 PMID: 16497588
  42. Higher-order substrate recognition of eIF2alpha by the RNA-dependent protein kinase PKR.
    Cell. 2005 Sep 23;122(6):887-900 PMID: 16179258
  43. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.
    Science. 2006 Nov 10;314(5801):997-1001 PMID: 17038589
  44. Translational insensitivity to potent activation of PKR by HCV IRES RNA.
    Antiviral Res. 2009 Sep;83(3):228-37 PMID: 19467267
  45. Structure and function of the protein kinase R.
    Curr Top Microbiol Immunol. 2007;316:253-92 PMID: 17969452
  46. The dsRNA protein kinase PKR: virus and cell control.
    Biochimie. 2007 Jun-Jul;89(6-7):799-811 PMID: 17451862
  47. Activation of PKR: an open and shut case?
    Trends Biochem Sci. 2007 Feb;32(2):57-62 PMID: 17196820
  48. In vitro activation of the interferon-induced, double-stranded RNA-dependent protein kinase PKR by RNA from the 3' untranslated regions of human alpha-tropomyosin.
    Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):508-13 PMID: 8552671
  49. Structure of the double-stranded RNA-binding domain of the protein kinase PKR reveals the molecular basis of its dsRNA-mediated activation.
    EMBO J. 1998 Sep 15;17(18):5458-65 PMID: 9736623
  50. Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy.
    Nat Biotechnol. 2005 Feb;23(2):222-6 PMID: 15619617
  51. Systematic deletion of the adenovirus-associated RNAI terminal stem reveals a surprisingly active RNA inhibitor of double-stranded RNA-activated protein kinase.
    J Biol Chem. 2008 Jun 20;283(25):17485-93 PMID: 18430723
  52. Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation.
    Nucleic Acids Res. 2010 Sep;38(17):5884-92 PMID: 20457754
  53. Orchestration of the activation of protein kinase R by the RNA-binding motif.
    J Interferon Cytokine Res. 2010 Apr;30(4):195-204 PMID: 20377414
  54. Activation of the protein kinase PKR by short double-stranded RNAs with single-stranded tails.
    RNA. 2004 Dec;10(12):1934-45 PMID: 15547138
  55. RNA adenosine deaminase ADAR1 deficiency leads to increased activation of protein kinase PKR and reduced vesicular stomatitis virus growth following interferon treatment.
    Virology. 2010 Jan 20;396(2):316-22 PMID: 19913273
  56. Activation of the interferon system by short-interfering RNAs.
    Nat Cell Biol. 2003 Sep;5(9):834-9 PMID: 12942087
  57. Mechanism of PKR Activation by dsRNA.
    J Mol Biol. 2008 Aug 29;381(2):351-60 PMID: 18599071
  58. Minor-groove recognition of double-stranded RNA by the double-stranded RNA-binding domain from the RNA-activated protein kinase PKR.
    Biochemistry. 1996 Aug 6;35(31):9983-94 PMID: 8756460
  59. Mechanism of interaction of the double-stranded RNA (dsRNA) binding domain of protein kinase R with short dsRNA sequences.
    Biochemistry. 2007 Jan 9;46(1):55-65 PMID: 17198375
  60. 5'-Triphosphate RNA is the ligand for RIG-I.
    Science. 2006 Nov 10;314(5801):994-7 PMID: 17038590
  61. Structure, function, and evolution of adenovirus-associated RNA: a phylogenetic approach.
    J Virol. 1996 Aug;70(8):5083-99 PMID: 8764016
  62. ADAR editing in double-stranded UTRs and other noncoding RNA sequences.
    Trends Biochem Sci. 2010 Jul;35(7):377-83 PMID: 20382028
Article Info
Journal
Current opinion in structural biology
Abbr.
Curr Opin Struct Biol
ISSN
1879-033X
DOI
10.1016/j.sbi.2010.11.003
Published
2011-02-00
Epub
2010-00-08
Pages
119-27
Language
English
Region
England
NLM ID
9107784
PMCID
PMC3075410
Subset
IM
Grants
NIGMS NIH HHS · R01 GM058709 · United States
NIGMS NIH HHS · R01 GM058709-12 · United States
PHS HHS · R01-58709 · United States
External Links
PubMed source DOI: 10.1016/j.sbi.2010.11.003 PMC Full Text View journal details
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