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

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.

Antisense inhibition of selenoprotein synthesis by Zika virus may contribute to neurological disorders and microcephaly by mimicking SePP1 knockout and the genetic disease progressive cerebello-cerebral atrophy

“…In addition to our published results showing antisense targeting of TR isoforms by HIV-1 and Ebola [13], and the current results for ZIKV, we have found that a number of other RNA viruses show potential antisense anti-TR interactions, including avian influenza and mumps virus; some of these are shown in Fig. S4 in the online Supplemental Materials.…”

“…The results reported here suggesting that ZIKV virus (like several other pathogenic RNA viruses [13]), may engage in antisense interactions with the mRNA or pre-mRNA of isoforms of TR, a ubiquitous selenoprotein oxidoreductase, may provide a new explanation for the observed interactions between dietary selenium and the pathogenesis of viruses with RNA genomes. Antisense targeting of host TR isoforms leading to decreased TR protein levels could be an effective strategy for many RNA viruses.…”

“…The potential virus-host "natural antisense" interactions that we have identified for ZIKV and other RNA viruses could have several possible biochemical outcomes, the most likely being inhibition of protein synthesis from the target mRNA (either via mRNA degradation, or via inhibition at the ribosomal level without mRNA degradation [41]). In the case of HIV-1 and Ebola, we have also proposed that, via host mRNA "antisense tethering interactions", viruses may capture functional RNA sequence motifs, e.g., to enable the expression of hidden viral selenoprotein genes, by recoding a conserved 3'-terminal UGA stop codon to be translated as Sec [13]. Thus, viral RNA antisense interactions with selenoprotein mRNAs could directly perturb host selenium biochemistry by various mechanisms.…”

“…Significantly, we recently demonstrated potential virus-host RNA antisense interactions between Ebola and HIV-1 viral mRNAs and the mRNAs of several isoforms of human thioredoxin reductase (TR), which raises the possibility that this novel mechanism might contribute to the well-established role for selenium in the pathogenesis of a number of RNA virus infections [13]. Hence, we investigate here the possibility that ZIKV mRNA might target one or more human selenoprotein mRNAs by antisense, which could lead to knockdown of the target selenoprotein levels by either mRNA degradation, or, more likely, by inhibition of protein synthesis at the ribosomal level.…”

“…1 via demonstration of in vitro DNA hybridization of the cognate ZIKV:SePP1 pair of sequences. The procedure was essentially as described previously [13]. Briefly, synthetic single stranded ssDNA oligomers (Integrated DNA Technologies, Inc., Coralville, IA) were obtained, corresponding precisely to the ZIKV and SePP1 sequence fragments shown in Fig.…”