Influenza virus non-structural protein NS1 cooperatively binds virus-specific (+)-strand RNA sequences
2013
Soubieux, Denis
Non-structural protein NS1 of influenza viruses plays a major role in countering the interferon response of the host, and is involved in the metabolism of viral and cellular RNAs. Its multiple activities all require a functional RNA-binding domain. NS1 is generally thought to bind non-specifically to several viral and cellular RNAs, notably to double-stranded RNAs (dsRNAs). We asked whether NS1 could exhibit some sequence-specificity towards its RNA ligands, and performed an in vitro selection (SELEX) to isolate NS1-specific aptamers. We identified two virus-specific sequences that are characteristic of the viral RNAs of positive polarity. The first motif, AGCAAAAG, is strictly conserved at the 5’-end of all (+)-strand RNAs of influenzaviruses A. The second motif, UGAUUGAAG, is highly conserved in NS1-mRNA, 15 nucleotides downstream of NS1’s stop codon. In addition, most of NS1-aptamers had one or two symmetrically positioned copies of the 5’-GUAAC / 3’-CUUAG double-stranded motif, which closely resembles the canonical 5’-splice site. We characterized the interaction of NS1 with its RNA-aptamers and showed that NS1’s RNA-binding domain specifically recognizes both the sequence and structure of the virus-specific RNA-sequences. Cooperative binding of NS1’s RNA-binding domain leads to its oligomerization on the bound RNA. This strong and intimate interaction suggests that NS1 activity towards viral RNAs is much more specific than previously thought.
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