Limits...
Cellular Selenoprotein mRNA Tethering via Antisense Interactions with Ebola and HIV-1 mRNAs May Impact Host Selenium Biochemistry

View Article: PubMed Central - PubMed

ABSTRACT

Regulation of protein expression by non-coding RNAs typically involves effects on mRNA degradation and/or ribosomal translation. The possibility of virus-host mRNA-mRNA antisense tethering interactions (ATI) as a gain-of-function strategy, via the capture of functional RNA motifs, has not been hitherto considered. We present evidence that ATIs may be exploited by certain RNA viruses in order to tether the mRNAs of host selenoproteins, potentially exploiting the proximity of a captured host selenocysteine insertion sequence (SECIS) element to enable the expression of virally-encoded selenoprotein modules, via translation of in-frame UGA stop codons as selenocysteine. Computational analysis predicts thermodynamically stable ATIs between several widely expressed mammalian selenoprotein mRNAs (e.g., isoforms of thioredoxin reductase) and specific Ebola virus mRNAs, and HIV-1 mRNA, which we demonstrate via DNA gel shift assays. The probable functional significance of these ATIs is further supported by the observation that, in both viruses, they are located in close proximity to highly conserved in-frame UGA stop codons at the 3′ end of open reading frames that encode essential viral proteins (the HIV-1 nef protein and the Ebola nucleoprotein). Significantly, in HIV/AIDS patients, an inverse correlation between serum selenium and mortality has been repeatedly documented, and clinical benefits of selenium in the context of multi-micronutrient supplementation have been demonstrated in several well-controlled clinical trials. Hence, in the light of our findings, the possibility of a similar role for selenium in Ebola pathogenesis and treatment merits serious investigation.

No MeSH data available.


Predicted antisense interactions between regions of mRNAs of human thioredoxin reductases and viral mRNAs. These are shown as both RNA secondary structures and antisense sequence alignments. The RNA structures shown and computed interaction free energies in kcal/mol (numerals next to the structures) were generated using the RNAHybrid 2.2 program (see Methods). The antisense matches are: A. EBOV nucleoprotein mRNA (Ebv-2014-NP, green) vs. TR3 mRNA (TR3-human, red); B. HIV-1 (HIVnef/LTR, green) vs. TR1 (TR1-human, red); C. A typical imperfect microRNA interaction is included for comparison (Let-7 vs. a cellular target, the default example in RNAHybrid). The alignments A and B correspond exactly to the RNA secondary structures above; GU base pairs are indicated by a colon, and the highly conserved UGA stop codon of the HIV-1 nef gene is indicated by an asterisk. In alignment A, the letters in italics above and below the sequences correspond to genomic sequence variations between the 2014 EBOV (green) and the earliest 1976 EBOV isolates (black italics), and between human TR3 (red) and fruit bat TR3 (black italics); see text for a discussion of these mutations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4997913&req=5

Figure 1: Predicted antisense interactions between regions of mRNAs of human thioredoxin reductases and viral mRNAs. These are shown as both RNA secondary structures and antisense sequence alignments. The RNA structures shown and computed interaction free energies in kcal/mol (numerals next to the structures) were generated using the RNAHybrid 2.2 program (see Methods). The antisense matches are: A. EBOV nucleoprotein mRNA (Ebv-2014-NP, green) vs. TR3 mRNA (TR3-human, red); B. HIV-1 (HIVnef/LTR, green) vs. TR1 (TR1-human, red); C. A typical imperfect microRNA interaction is included for comparison (Let-7 vs. a cellular target, the default example in RNAHybrid). The alignments A and B correspond exactly to the RNA secondary structures above; GU base pairs are indicated by a colon, and the highly conserved UGA stop codon of the HIV-1 nef gene is indicated by an asterisk. In alignment A, the letters in italics above and below the sequences correspond to genomic sequence variations between the 2014 EBOV (green) and the earliest 1976 EBOV isolates (black italics), and between human TR3 (red) and fruit bat TR3 (black italics); see text for a discussion of these mutations.

Mentions: In this study, we present both computational and experimental evidence for antisense tethering interactions (ATIs) between host selenoprotein mRNAs (specifically, thioredoxin reductase mRNAs) and certain mRNAs of RNA viruses. We focus here on the two most compelling examples we have identified, one involving the highly pathogenic Zaire strain of Ebola virus (EBOV), and another involving HIV-1. The first, shown as A in (Fig. 1), is between the mRNA of the human thioredoxin reductase 3 (TR3) and the mRNA encoding the nucleoprotein (NP) of EBOV; the second (B in Fig. 1) is between the mRNA of human thioredoxin reductase 1 (TR1) and a region of HIV-1 genomic mRNA, in the 3′-long terminal repeat (LTR).


Cellular Selenoprotein mRNA Tethering via Antisense Interactions with Ebola and HIV-1 mRNAs May Impact Host Selenium Biochemistry
Predicted antisense interactions between regions of mRNAs of human thioredoxin reductases and viral mRNAs. These are shown as both RNA secondary structures and antisense sequence alignments. The RNA structures shown and computed interaction free energies in kcal/mol (numerals next to the structures) were generated using the RNAHybrid 2.2 program (see Methods). The antisense matches are: A. EBOV nucleoprotein mRNA (Ebv-2014-NP, green) vs. TR3 mRNA (TR3-human, red); B. HIV-1 (HIVnef/LTR, green) vs. TR1 (TR1-human, red); C. A typical imperfect microRNA interaction is included for comparison (Let-7 vs. a cellular target, the default example in RNAHybrid). The alignments A and B correspond exactly to the RNA secondary structures above; GU base pairs are indicated by a colon, and the highly conserved UGA stop codon of the HIV-1 nef gene is indicated by an asterisk. In alignment A, the letters in italics above and below the sequences correspond to genomic sequence variations between the 2014 EBOV (green) and the earliest 1976 EBOV isolates (black italics), and between human TR3 (red) and fruit bat TR3 (black italics); see text for a discussion of these mutations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997913&req=5

Figure 1: Predicted antisense interactions between regions of mRNAs of human thioredoxin reductases and viral mRNAs. These are shown as both RNA secondary structures and antisense sequence alignments. The RNA structures shown and computed interaction free energies in kcal/mol (numerals next to the structures) were generated using the RNAHybrid 2.2 program (see Methods). The antisense matches are: A. EBOV nucleoprotein mRNA (Ebv-2014-NP, green) vs. TR3 mRNA (TR3-human, red); B. HIV-1 (HIVnef/LTR, green) vs. TR1 (TR1-human, red); C. A typical imperfect microRNA interaction is included for comparison (Let-7 vs. a cellular target, the default example in RNAHybrid). The alignments A and B correspond exactly to the RNA secondary structures above; GU base pairs are indicated by a colon, and the highly conserved UGA stop codon of the HIV-1 nef gene is indicated by an asterisk. In alignment A, the letters in italics above and below the sequences correspond to genomic sequence variations between the 2014 EBOV (green) and the earliest 1976 EBOV isolates (black italics), and between human TR3 (red) and fruit bat TR3 (black italics); see text for a discussion of these mutations.
Mentions: In this study, we present both computational and experimental evidence for antisense tethering interactions (ATIs) between host selenoprotein mRNAs (specifically, thioredoxin reductase mRNAs) and certain mRNAs of RNA viruses. We focus here on the two most compelling examples we have identified, one involving the highly pathogenic Zaire strain of Ebola virus (EBOV), and another involving HIV-1. The first, shown as A in (Fig. 1), is between the mRNA of the human thioredoxin reductase 3 (TR3) and the mRNA encoding the nucleoprotein (NP) of EBOV; the second (B in Fig. 1) is between the mRNA of human thioredoxin reductase 1 (TR1) and a region of HIV-1 genomic mRNA, in the 3′-long terminal repeat (LTR).

View Article: PubMed Central - PubMed

ABSTRACT

Regulation of protein expression by non-coding RNAs typically involves effects on mRNA degradation and/or ribosomal translation. The possibility of virus-host mRNA-mRNA antisense tethering interactions (ATI) as a gain-of-function strategy, via the capture of functional RNA motifs, has not been hitherto considered. We present evidence that ATIs may be exploited by certain RNA viruses in order to tether the mRNAs of host selenoproteins, potentially exploiting the proximity of a captured host selenocysteine insertion sequence (SECIS) element to enable the expression of virally-encoded selenoprotein modules, via translation of in-frame UGA stop codons as selenocysteine. Computational analysis predicts thermodynamically stable ATIs between several widely expressed mammalian selenoprotein mRNAs (e.g., isoforms of thioredoxin reductase) and specific Ebola virus mRNAs, and HIV-1 mRNA, which we demonstrate via DNA gel shift assays. The probable functional significance of these ATIs is further supported by the observation that, in both viruses, they are located in close proximity to highly conserved in-frame UGA stop codons at the 3′ end of open reading frames that encode essential viral proteins (the HIV-1 nef protein and the Ebola nucleoprotein). Significantly, in HIV/AIDS patients, an inverse correlation between serum selenium and mortality has been repeatedly documented, and clinical benefits of selenium in the context of multi-micronutrient supplementation have been demonstrated in several well-controlled clinical trials. Hence, in the light of our findings, the possibility of a similar role for selenium in Ebola pathogenesis and treatment merits serious investigation.

No MeSH data available.