Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use

Atkins, John F.; Loughran, Gary; Bhatt, Pramod R.; Firth, Andrew E.; Baranov, Pavel V.

Influenza A virus utilizes ribosomal frameshifting with important consequences (39). The directionality of the shift, +1, is different from that used by the viruses considered above, all of which are −1. While sites utilized for +1 frameshifting 5 adjacent to stop codons were previously known in chromosomal gene expression, +1 frameshift sites at internal positions are notoriously difficult to spot. The previously unrecognized type of site utilized by influenza A virus has provided guides for spotting the sites of other occurrences of +1 frameshifting including that for important chronic bee paralysis virus, related viruses such as Lake Sinai virus (125) and members of the Amalgaviridae family (126) . Influenza A virus is a single-stranded negative-sense, segmented RNA virus and the frameshifting occurs in decoding its segment 3. This segment yields a single mRNA that encodes a subunit of the viral RNA-dependent RNA polymerase. The frameshift-derived product, PA-X, has the same endonuclease domain as the polymerase subunit but lacks the C-terminal region needed for association with other subunits. Key amino acids encoded by the frameshiftderived segment that are important for the host shut-off function have already been identified (127) . In some viral strains the +1 frame encoded C-terminal extension is 41 amino acids and in others it is 61 (39). There is evidence for host species specificity with increasing prevelance of the shorter form in pigs for characterized reasons (128) . Potential significance derives from avian influenza viruses infecting pigs that serve as 'mixing vessels' for the generation of novel influenza viruses with pandemic potential. Effects of PA-X on depletion of poly(A) RNA (129) , and in particular on specific host RNA polymerase II transcripts (130) , have been characterized. Though strain-specific (131), for some viral strains PA-X deficient viruses display higher virulence in mice than isogenic WT viruses (39, 131) , in contrast to the effects of disabling several other cases of viral frameshifting. No signals for stimulating frameshifting at the shift site are evident and correspondingly the level of frameshifting is very low. It is salutory that despite this very low level of the frameshifting, the frameshift derived product significantly modulates host expression. Its loss leads to changes in the kinetics of the global host response including increases in inflammatory, apoptotic and T lymphocyte-signaling pathways (39).