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Article ; Online: Nucleoside modifications modulate activation of the protein kinase PKR in an RNA structure-specific manner.

Nallagatla, Subba Rao / Bevilacqua, Philip C

2008 Volume 14, Issue 6, Page(s) 1201–1213

Abstract: The human interferon-induced protein kinase PKR is a key component of innate immunity, a process in which it senses pathogenic RNA. PKR consists of an N-terminal dsRNA-binding domain (dsRBD) and a C-terminal kinase domain. Upon binding long (>33 base ... ...

Abstract	The human interferon-induced protein kinase PKR is a key component of innate immunity, a process in which it senses pathogenic RNA. PKR consists of an N-terminal dsRNA-binding domain (dsRBD) and a C-terminal kinase domain. Upon binding long (>33 base pairs) stretches of pathogenic dsRNA, PKR undergoes autophosphorylation, which activates it to phosphorylate eIF2alpha, leading to inhibition of translation initiation. Many cellular and viral transcripts contain nucleoside modifications, and these could affect PKR activation. For example, a 5'-triphosphate confers the ability of relatively unstructured transcripts to activate PKR. Effects of internal RNA modifications on PKR activation have not been reported. Herein, PKR activation by ssRNA and dsRNA containing internal nucleobase, sugar, and phosphodiester modifications is analyzed. We find that for 5'-triphosphate-containing ssRNA, most base and sugar modifications abrogate activation, although 2'-fluoro-modified ssRNA does not, indicative of a critical role for hydrogen bonding at the ribose sugar. In the case of dsRNA, a more limited set of nucleoside modifications affect PKR activation. Watson-Crick base-pairing is required for activation, and some minor groove modifications abrogate activation while major groove modifications have little effect. Surprisingly, GU wobble pairs also largely abrogate dsRNA-mediated activation when present at modest levels. Modifications to dsRNA that abrogate activation have no significant effect on dsRBD binding, allowing such RNAs to act as inhibitors and suggesting a nonequivalence of binding ability and activation. Overall, the findings indicate that nucleoside modifications and wobble pairing may serve to discriminate self-RNA and pathogenic RNA in innate immunity.
MeSH term(s)	Base Pairing ; Base Sequence ; Enzyme Activation ; Humans ; Hydrogen Bonding ; Molecular Sequence Data ; Nucleic Acid Conformation ; Nucleosides/chemistry ; Nucleosides/metabolism ; Phosphorylation ; Polyphosphates/chemistry ; Polyphosphates/metabolism ; RNA/chemistry ; RNA/metabolism ; RNA, Double-Stranded/chemistry ; RNA, Double-Stranded/metabolism ; Ribose/chemistry ; Ribose/metabolism ; eIF-2 Kinase/antagonists & inhibitors ; eIF-2 Kinase/chemistry ; eIF-2 Kinase/metabolism
Chemical Substances	Nucleosides ; Polyphosphates ; RNA, Double-Stranded ; RNA (63231-63-0) ; Ribose (681HV46001) ; eIF-2 Kinase (EC 2.7.11.1) ; triphosphoric acid (NU43IAG5BC)
Language	English
Publishing date	2008-04-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.1007408
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Article: Regulation of innate immunity through RNA structure and the protein kinase PKR

Nallagatla, Subba Rao / Toroney, Rebecca / Bevilacqua, Philip C

Current Opinion in Structural Biology. 2011 Feb., v. 21, no. 1

2011

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 ... ...

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.
Keywords	dimerization ; double-stranded RNA ; innate immunity ; prediction ; protein kinases ; protein structure ; small interfering RNA
Language	English
Dates of publication	2011-02
Size	p. 119-127.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1068353-7
ISSN	0959-440X
ISSN	0959-440X
DOI	10.1016/j.sbi.2010.11.003
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Regulation of innate immunity through RNA structure and the protein kinase PKR.

Nallagatla, Subba Rao / Toroney, Rebecca / Bevilacqua, Philip C

Current opinion in structural biology

2010 Volume 21, Issue 1, Page(s) 119–127

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 term(s)	Animals ; Enzyme Activation ; Humans ; Immunity, Innate ; Nucleic Acid Conformation ; RNA/chemistry ; RNA/metabolism ; eIF-2 Kinase/metabolism
Chemical Substances	RNA (63231-63-0) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2010-12-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2010.11.003
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Article ; Online: RNA helical imperfections regulate activation of the protein kinase PKR: effects of bulge position, size, and geometry.

Heinicke, Laurie A / Nallagatla, Subba Rao / Hull, Chelsea M / Bevilacqua, Philip C

RNA (New York, N.Y.)

2011 Volume 17, Issue 5, Page(s) 957–966

Abstract: The protein kinase, PKR, is activated by long stretches of double-stranded (ds) RNA. Viruses often make long dsRNA elements with imperfections that still activate PKR. However, due to the complexity of the RNA structure, prediction of whether a given RNA ...

Abstract	The protein kinase, PKR, is activated by long stretches of double-stranded (ds) RNA. Viruses often make long dsRNA elements with imperfections that still activate PKR. However, due to the complexity of the RNA structure, prediction of whether a given RNA is an activator of PKR is difficult. Herein, we systematically investigated how various RNA secondary structure defects contained within model dsRNA affect PKR activation. We find that bulges increasingly disfavor activation as they are moved toward the center of a duplex and as they are increased in size. Model RNAs designed to conform to cis, trans, or bent global geometries through strategic positioning of one or more bulges decreased activation of PKR relative to perfect dsRNA, although cis-bulged RNAs activated PKR much more potently than trans-bulged RNAs. Activation studies on bulge-containing chimeric duplexes support a model wherein PKR monomers interact adjacently, rather than through-space, for activation on bulged substrates. Last, unusually low ionic strength induced substantial increases in PKR activation in the presence of bulged RNAs suggesting that discrimination against bulges is higher under biological ionic strength conditions. Overall, this study provides a set of rules for understanding how secondary structural defects affect PKR activity.
MeSH term(s)	Base Sequence ; Enzyme Activation ; Kinetics ; Molecular Sequence Data ; Nucleic Acid Conformation ; Osmolar Concentration ; Protein Multimerization ; RNA, Double-Stranded/chemistry ; eIF-2 Kinase/metabolism
Chemical Substances	RNA, Double-Stranded ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2011-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.2636911
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Article ; Online: A brilliant disguise for self RNA: 5'-end and internal modifications of primary transcripts suppress elements of innate immunity.

Nallagatla, Subba Rao / Toroney, Rebecca / Bevilacqua, Philip C

RNA biology

2008 Volume 5, Issue 3, Page(s) 140–144

Abstract: Interferon inducible protein kinase PKR is a component of innate immunity and mediates antiviral actions by recognizing pathogen associated molecular patterns (PAMPs). A well-known activator of PKR is long dsRNA, which can be produced during viral ... ...

Abstract	Interferon inducible protein kinase PKR is a component of innate immunity and mediates antiviral actions by recognizing pathogen associated molecular patterns (PAMPs). A well-known activator of PKR is long dsRNA, which can be produced during viral replication. Our recent results indicate that PKR can also be activated by short stem-loop RNA in a 5'-triphosphate-dependent fashion. A 5'-triphosphate is present primarily in foreign RNAs such as viral and bacterial transcripts, while a non-activating 5'-cap or 5'-monophosphate is present in most cellular RNAs. Additional studies indicate that internal RNA modifications and non-Watson-Crick motifs also repress PKR activation, and do so in an RNA structure-specific fashion. Interestingly, self-RNAs have more nucleoside modifications than non-self RNAs. Internal and 5'-end RNA modifications have repressive effects on other innate immune sensors as well, including TLR3, TLR7, TLR8, and RIG-I, suggesting that nucleoside modifications suppress innate immunity on a wide scale.
MeSH term(s)	Animals ; Humans ; Immunity, Innate/genetics ; RNA, Messenger/metabolism ; Receptors, Pattern Recognition/metabolism ; Toll-Like Receptors/metabolism ; eIF-2 Kinase/metabolism
Chemical Substances	RNA, Messenger ; Receptors, Pattern Recognition ; Toll-Like Receptors ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2008-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1555-8584
ISSN (online)	1555-8584
DOI	10.4161/rna.5.3.6839
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Article: A brilliant disguise for self RNA: 5’-end and internal modifications of primary transcripts suppress elements of innate immunity

Nallagatla, Subba Rao / Toroney, Rebecca / Bevilacqua, Philip C

RNA biology. 2008 July 1, v. 5, no. 3

2008

Abstract	Interferon inducible protein kinase PKR is a component of innate immunity and mediates antiviral actions by recognizing pathogen associated molecular patterns (PAMPs). A well-known activator of PKR is long dsRNA, which can be produced during viral replication. Our recent results indicate that PKR can also be activated by short stem-loop RNA in a 5’-triphosphate-dependent fashion. A 5’-triphosphate is present primarily in foreign RNAs such as viral and bacterial transcripts, while a non-activating 5’-cap or 5’-monophosphate is present in most cellular RNAs. Recent studies indicate that internal RNA modifications and non-Watson-Crick motifs also repress PKR activation, and do so in an RNA structure-specific fashion. Interestingly, self-RNAs have more nucleoside modifications than non-self RNAs. Internal and 5’-end RNA modifications have repressive effects on other innate immune sensors as well, including TLR3, TLR7, TLR8, and RIG-I, suggesting that nucleoside modifications suppress innate immunity on a wide scale. (144/150)
Keywords	Toll-like receptor 3 ; Toll-like receptor 7 ; Toll-like receptor 8 ; antiviral properties ; double-stranded RNA ; innate immunity ; interferons ; messenger RNA ; nucleosides ; pathogen-associated molecular patterns ; protein kinases ; virus replication
Language	English
Dates of publication	2008-0701
Size	p. 140-144.
Publishing place	Taylor & Francis
Document type	Article
ISSN	1555-8584
DOI	10.4161/rna.5.3.6839
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Combinatorial synthesis of thrombin-binding aptamers containing iso-guanine.

Nallagatla, Subba Rao / Heuberger, Benjamin / Haque, Azizul / Switzer, Christopher

Journal of combinatorial chemistry

2009 Volume 11, Issue 3, Page(s) 364–369

Abstract: A library of all possible substitutions of guanine by iso-guanine (iG) in the thrombin aptamer was prepared by split and mix synthesis. A colorimetric assay was used to screen for functional oligomers in the library. Colorimetrically active ... ...

Abstract	A library of all possible substitutions of guanine by iso-guanine (iG) in the thrombin aptamer was prepared by split and mix synthesis. A colorimetric assay was used to screen for functional oligomers in the library. Colorimetrically active oligonucleotides were selected and sequenced by the Maxam-Gilbert method. The sequenced oligonucleotides were individually resynthesized, and their affinities for thrombin were assayed by isothermal titration calorimetry. Three aptamer sequences containing iG were found to have enhanced binding activity to human alpha-thrombin compared to the parent aptamer.
MeSH term(s)	Aptamers, Nucleotide/chemical synthesis ; Aptamers, Nucleotide/chemistry ; Aptamers, Nucleotide/metabolism ; Calorimetry ; Colorimetry ; Combinatorial Chemistry Techniques/methods ; Guanine/chemical synthesis ; Guanine/chemistry ; Humans ; Isomerism ; Models, Molecular ; Oligonucleotides/chemical synthesis ; Oligonucleotides/chemistry ; Oligonucleotides/metabolism ; Protein Binding ; Thrombin/metabolism ; Titrimetry
Chemical Substances	Aptamers, Nucleotide ; Oligonucleotides ; thrombin aptamer (145563-68-4) ; Guanine (5Z93L87A1R) ; Thrombin (EC 3.4.21.5)
Language	English
Publishing date	2009-05
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1520-4774
ISSN (online)	1520-4774
DOI	10.1021/cc800178m
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Native tertiary structure and nucleoside modifications suppress tRNA's intrinsic ability to activate the innate immune sensor PKR.

Nallagatla, Subba Rao / Jones, Christie N / Ghosh, Saikat Kumar B / Sharma, Suresh D / Cameron, Craig E / Spremulli, Linda L / Bevilacqua, Philip C

PloS one

2013 Volume 8, Issue 3, Page(s) e57905

Abstract: Interferon inducible protein kinase PKR is an essential component of innate immunity. It is activated by long stretches of dsRNA and provides the first line of host defense against pathogens by inhibiting translation initiation in the infected cell. Many ...

Abstract	Interferon inducible protein kinase PKR is an essential component of innate immunity. It is activated by long stretches of dsRNA and provides the first line of host defense against pathogens by inhibiting translation initiation in the infected cell. Many cellular and viral transcripts contain nucleoside modifications and/or tertiary structure that could affect PKR activation. We have previously demonstrated that a 5'-end triphosphate-a signature of certain viral and bacterial transcripts-confers the ability of relatively unstructured model RNA transcripts to activate PKR to inhibit translation, and that this activation is abrogated by certain modifications present in cellular RNAs. In order to understand the biological implications of native RNA tertiary structure and nucleoside modifications on PKR activation, we study here the heavily modified cellular tRNAs and the unmodified or the lightly modified mitochondrial tRNAs (mt-tRNA). We find that both a T7 transcript of yeast tRNA(Phe) and natively extracted total bovine liver mt-tRNA activate PKR in vitro, whereas native E. coli, bovine liver, yeast, and wheat tRNA(Phe) do not, nor do a variety of base- or sugar-modified T7 transcripts. These results are further supported by activation of PKR by a natively folded T7 transcript of tRNA(Phe)in vivo supporting the importance of tRNA modification in suppressing PKR activation in cells. We also examine PKR activation by a T7 transcript of the A14G pathogenic mutant of mt-tRNA(Leu), which is known to dimerize, and find that the misfolded dimeric form activates PKR in vitro while the monomeric form does not. Overall, the in vitro and in vivo findings herein indicate that tRNAs have an intrinsic ability to activate PKR and that nucleoside modifications and native RNA tertiary folding may function, at least in part, to suppress such activation, thus serving to distinguish self and non-self tRNA in innate immunity.
MeSH term(s)	Animals ; Base Sequence ; Cattle ; Cell Line, Tumor ; Dimerization ; Enzyme Activation ; Humans ; Immunity, Innate/immunology ; Molecular Sequence Data ; Mutation/genetics ; Nucleic Acid Conformation ; Nucleosides/metabolism ; Protein Binding ; RNA/chemistry ; RNA/genetics ; RNA, Mitochondrial ; RNA, Transfer/chemistry ; RNA, Transfer/genetics ; RNA, Transfer/metabolism ; Saccharomyces cerevisiae/metabolism ; eIF-2 Kinase/metabolism
Chemical Substances	Nucleosides ; RNA, Mitochondrial ; RNA (63231-63-0) ; RNA, Transfer (9014-25-9) ; eIF-2 Kinase (EC 2.7.11.1)
Keywords	covid19
Language	English
Publishing date	2013-03-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0057905
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Article ; Online: Regulation of PKR by HCV IRES RNA: importance of domain II and NS5A.

Toroney, Rebecca / Nallagatla, Subba Rao / Boyer, Joshua A / Cameron, Craig E / Bevilacqua, Philip C

Journal of molecular biology

2010 Volume 400, Issue 3, Page(s) 393–412

Abstract: Protein kinase R (PKR) is an essential component of the innate immune response. In the presence of double-stranded RNA (dsRNA), PKR is autophosphorylated, which enables it to phosphorylate its substrate, eukaryotic initiation factor 2alpha, leading to ... ...

Abstract	Protein kinase R (PKR) is an essential component of the innate immune response. In the presence of double-stranded RNA (dsRNA), PKR is autophosphorylated, which enables it to phosphorylate its substrate, eukaryotic initiation factor 2alpha, leading to translation cessation. Typical activators of PKR are long dsRNAs produced during viral infection, although certain other RNAs can also activate. A recent study indicated that full-length internal ribosome entry site (IRES), present in the 5'-untranslated region of hepatitis C virus (HCV) RNA, inhibits PKR, while another showed that it activates. We show here that both activation and inhibition by full-length IRES are possible. The HCV IRES has a complex secondary structure comprising four domains. While it has been demonstrated that domains III-IV activate PKR, we report here that domain II of the IRES also potently activates. Structure mapping and mutational analysis of domain II indicate that while the double-stranded regions of the RNA are important for activation, loop regions contribute as well. Structural comparison reveals that domain II has multiple, non-Watson-Crick features that mimic A-form dsRNA. The canonical and noncanonical features of domain II cumulate to a total of approximately 33 unbranched base pairs, the minimum length of dsRNA required for PKR activation. These results provide further insight into the structural basis of PKR activation by a diverse array of RNA structural motifs that deviate from the long helical stretches found in traditional PKR activators. Activation of PKR by domain II of the HCV IRES has implications for the innate immune response when the other domains of the IRES may be inaccessible. We also study the ability of the HCV nonstructural protein 5A (NS5A) to bind various domains of the IRES and alter activation. A model is presented for how domain II of the IRES and NS5A operate to control host and viral translation during HCV infection.
MeSH term(s)	Base Sequence ; Hepacivirus/physiology ; Models, Molecular ; Molecular Sequence Data ; Nucleic Acid Conformation ; Point Mutation ; Protein Binding ; RNA, Viral/metabolism ; Viral Nonstructural Proteins/metabolism ; eIF-2 Kinase/metabolism
Chemical Substances	RNA, Viral ; Viral Nonstructural Proteins ; eIF-2 Kinase (EC 2.7.11.1) ; NS-5 protein, hepatitis C virus (EC 2.7.7.48)
Language	English
Publishing date	2010-05-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2010.04.059
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Article ; Online: 5'-triphosphate-dependent activation of PKR by RNAs with short stem-loops.

Nallagatla, Subba Rao / Hwang, Jungwook / Toroney, Rebecca / Zheng, Xiaofeng / Cameron, Craig E / Bevilacqua, Philip C

Science (New York, N.Y.)

2007 Volume 318, Issue 5855, Page(s) 1455–1458

Abstract: Molecular patterns in pathogenic RNAs can be recognized by the innate immune system, and a component of this response is the interferon-induced enzyme RNA-activated protein kinase (PKR). The major activators of PKR have been proposed to be long double- ... ...

Abstract	Molecular patterns in pathogenic RNAs can be recognized by the innate immune system, and a component of this response is the interferon-induced enzyme RNA-activated protein kinase (PKR). The major activators of PKR have been proposed to be long double-stranded RNAs. We report that RNAs with very limited secondary structures activate PKR in a 5'-triphosphate-dependent fashion in vitro and in vivo. Activation of PKR by 5'-triphosphate RNA is independent of RIG-I and is enhanced by treatment with type 1 interferon (IFN-alpha). Surveillance of molecular features at the 5' end of transcripts by PKR presents a means of allowing pathogenic RNA to be distinguished from self-RNA. The evidence presented here suggests that this form of RNA-based discrimination may be a critical step in mounting an early immune response.
MeSH term(s)	Animals ; Base Sequence ; Cell Line, Tumor ; Chlorocebus aethiops ; DEAD Box Protein 58 ; DEAD-box RNA Helicases/metabolism ; Enzyme Activation ; Eukaryotic Initiation Factor-2/metabolism ; Humans ; Immunity, Innate ; Interferon-alpha/immunology ; Interferon-alpha/metabolism ; Interferon-beta/metabolism ; Molecular Sequence Data ; Nucleic Acid Conformation ; Phosphoric Monoester Hydrolases/metabolism ; Polyphosphates/metabolism ; RNA/chemistry ; RNA/genetics ; RNA/metabolism ; RNA, Double-Stranded/chemistry ; RNA, Double-Stranded/genetics ; RNA, Double-Stranded/metabolism ; Receptors, Immunologic ; Transfection ; Vero Cells ; eIF-2 Kinase/metabolism
Chemical Substances	Eukaryotic Initiation Factor-2 ; Interferon-alpha ; Polyphosphates ; RNA, Double-Stranded ; Receptors, Immunologic ; RNA (63231-63-0) ; Interferon-beta (77238-31-4) ; eIF-2 Kinase (EC 2.7.11.1) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; RIGI protein, human (EC 3.6.1.-) ; DEAD Box Protein 58 (EC 3.6.4.13) ; DEAD-box RNA Helicases (EC 3.6.4.13) ; triphosphoric acid (NU43IAG5BC)
Language	English
Publishing date	2007-11-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.1147347
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