Poly I:c, an Inducer of Interferon and Interference Against Virus Infections

Ak, Field; Aa, Tytell; Piperno, E; Gp, Lampson; Mm, Nemes; Mr, Hilleman

doi:10.1097/00005792-197205000-00002

Cited by 26 publications

(13 citation statements)

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“…Greater reduction in the average molecular weight of rC, brought about by treatment with pancreatic RNase did result in gradually decreased capacity to form complexes with high molecular weight rI, and this was accompanied by reduced capacity to induce interferon and resistance to viruses. These results reaffirm the initial observations (4)(5)(6)(7)(8)(9) by our group that doublestrandedness of polynucleotides is necessary to demonstrate interferon induction and host resistance. Reduction in or loss of capacity to form doublestranded complexes diminished or eliminated the capacity to induce interferon and resistance.…”

supporting

confidence: 89%

Influence of Size of Individual Homopolynucleotides on the Physical and Biological Properties of Complexed rIn:rCn (Poly I:C)

Aa¹,

Gp²,

Ak³

et al. 1970

Experimental Biology and Medicine

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A separate report from these laboratories (1) described the findings in investigations to measure the effect of reduction of molecular weight of rIn:rCn (poly 1:C) complexes on their physical, chemical, and biological properties. The present report describes the influence of the molecular sizes of the individual homopolymers (rI, and rCn) on their ability to form the double-stranded complex (rIn:rCn) and to induce interferon and resistance to viral infections.Materials and Methods. Sources of polyribonucleotides. Polyriboinosinic acid (rI,) , and polyribocytidylic acid (rC,) with sedimentation coefficients of 12.3 and 13.2 respectively, were purchased from the P-L Laboratories, Milwaukee, Wisconsin. The dephosphoryla ted oligo-inosinic acid trimer (Ip) zI and the dephosphorylated oligocytidylic acid pentamer (Cp) *C were obtained from Miles Laboraltories, Elkhart, Indiana, All other polynucleotides were prepared by Drs. J. L. Zabriskie and E. E. Harris of the Merck Process ResearchGroup. Treatment of polyribonucleotides. Sonic radiation of the homopolymers to reduce molecular size was carried out by procedures described earlier ( 1 ) . Ribonuclease ( RNase) degradation of rC, was carried out as follows: rC, with Sw,20 of 9.2 (mol wt = 1.9 X lo5) was dissolved in 01.15 M NaC1-01.0106 M sodium phosphate buffer solution (PBS), pH 7.0, at a concentration of 1 mg/ml and was incubated with pancreatic ribonuclease A (Sigma Chemical Co., St. Louis, Mo.) at a concentration of 0.01 or 0.1 pg/ml at 23' for varying time intervals. Samples were removed and complexed with rI, (mol wt = 1.9

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supporting

confidence: 89%

Influence of Size of Individual Homopolynucleotides on the Physical and Biological Properties of Complexed rIn:rCn (Poly I:C)

Aa¹,

Gp²,

Ak³

et al. 1970

Experimental Biology and Medicine

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“…Double-stranded RNA's of synthetic or natural origin with greatly different thermal stabilities have been shown (10,12) to have comparable interferon inducing capacities. It would appear, therefore, that thermal stability plays only a minor role in determining the inductive capacity of double-stranded RNA beyond a minimal thermal stability level which is sufficient to maintain doublestrandedness under physiological conditions.…”

mentioning

confidence: 99%

Relationship of Molecular Size of rIn:rCn (Poly I:C) to Induction of Interferon and Host Resistance

Gp¹,

Ak²,

Aa³

et al. 1970

Experimental Biology and Medicine

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“…6, C and E). Viral infections may also induce stress granules, and transfection of cells with long double-stranded RNA (poly(I:C)) can be used as a mimic (30). Poly(I:C) transfection gave stress granules in a subset of cells not seen after mock (Fig.…”

Section: Journal Of Biological Chemistry 21789mentioning

confidence: 99%

Regulation of Human Endonuclease V Activity and Relocalization to Cytoplasmic Stress Granules

Nawaz

Vik

Berges

et al. 2016

Journal of Biological Chemistry

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Endonuclease V (EndoV) is an enzyme with specificity for inosines in nucleic acids. Whereas the bacterial homologs are active on both DNA and RNA, the mammalian variants only cleave RNA, at least when assayed with recombinant proteins. Here we show that ectopically expressed, as well as endogenously expressed human (h)EndoV, share the same enzymatic properties as the recombinant protein and cleaves RNA with inosine but not DNA. In search for proteins interacting with hEndoV, polyadenylate-binding protein C1 (PABPC1) was identified. The association between PABPC1 and hEndoV is RNA dependent and furthermore, PABPC1 stimulates hEndoV activity and affinity for inosine-containing RNA. Upon cellular stress, PABPC1 relocates to cytoplasmic stress granules that are multimolecular aggregates of stalled translation initiation complexes formed to aid cell recovery. Arsenite, as well as other agents, triggered relocalization also of hEndoV to cytoplasmic stress granules. As inosines in RNA are highly abundant, hEndoV activity is likely regulated in cells to avoid aberrant cleavage of inosine-containing transcripts. Indeed, we find that hEndoV cleavage is inhibited by normal intracellular ATP concentrations. The ATP stores inside a cell do not overlay stress granules and we suggest that hEndoV is redistributed to stress granules as a strategy to create a local environment low in ATP to permit hEndoV activity.Deamination of adenosine (A) to inosine (I) is a reaction that occurs spontaneously in cells and is enhanced by exposure to nitrosative agents formed as a response to inflammation, infection, or from the environment (1, 2). Both DNA and RNA as well as unincorporated (deoxy)ribonucleotides are subjected to deamination (3). Inosine is read as guanosine (G) by cellular proteins, and in DNA this event is thus considered mutagenic (3, 4). Consequences of adenosine deamination in RNA depend on which type and part of a transcript is deaminated and may result in altered coding, splicing, stability, and structure of an RNA or in intracellular relocalization (5).In addition to arbitrary deamination events, inosine is also introduced in RNA by specific enzymes in a highly regulated manner to increase transcriptomic diversity (6). Responsible enzymes are the adenosine deaminases acting on RNA (ADARs) 2 that catalyze A to I editing on mRNA and non-coding (nc)RNA including long ncRNA, micro (mi)RNA and small interfering (si)RNA. A to I editing is abundant in higher eukaryotes and edited sites amount to more than 100 million and are spread over the majority of human genes (7). Defective editing is linked to various human diseases including neurological disorders, infections, and cancer (8 -11). Also some tRNAs undergo A to I editing at the anticodon wobble adenosine A 34 , a reaction that is catalyzed by adenosine deaminases acting on tRNA (ADATs) (12). ADATs are homologs to the ADARs and their editing is essential for protein synthesis (12, 13).Until recently, no enzymatic activity specific for inosine in RNA was known. However, endon...

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Poly I:c, an Inducer of Interferon and Interference Against Virus Infections

Cited by 26 publications

References 0 publications

Influence of Size of Individual Homopolynucleotides on the Physical and Biological Properties of Complexed rIn:rCn (Poly I:C)

Influence of Size of Individual Homopolynucleotides on the Physical and Biological Properties of Complexed rIn:rCn (Poly I:C)

Relationship of Molecular Size of rIn:rCn (Poly I:C) to Induction of Interferon and Host Resistance

Regulation of Human Endonuclease V Activity and Relocalization to Cytoplasmic Stress Granules

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