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.

Many different Gram negative bacteria that interact with plants or animals use a Type III secretion system, or injectosome, to inject proteins into host cells for initial hijacking of their functions. Another ca. 25 proteins including transcription activators, are used to build the secretion system. In Shigella, which causes human dysentery, the encoding genes are plasmid-borne. After transcribing the first 58 codons of spa13, transcriptional slippage yields mRNA that results in 25 to 30% of the product having a C-terminal extension of 112 AA required for secretion system function. The encoding sequence for the end of this extension overlaps the start of spa32 and transcriptional slippage in spa13 has a major effect on spa32 expression (326). Spa32 is very important in the determination of the length of the hollow extracellular needle that forms the injection conduit (327). Spa32's role in length determination is affected by its interaction with Spa40 that also interacts with 5 other proteins including Spa33 and MxiA (328). Expression of spa33 and mxiA also involves transcription slippage but in these cases it yields truncated products (326). In addition, slippage to yield an extended product occurs in the expression of the regulator gene mxiE with substantial effects on the expression of the adjacent downstream gene (329). Whether the modulatory effect of the transcription slippage on the ratio of the products is influenced by environmental conditions is unknown. While this type III secretion system mechanism is different from phage lambda GT ribosomal frameshifting, expression of the Yersinia pestis and Y. pseudotuberculosis YopN-TyeA fusion protein related to function of its type III system is also at the ribosomal frameshifting level (330,331). Y. pestis, the etiological agent of the infamous plague, is still a major human problem in several countries (332) and Y. pseudotuberculosis is a less aggressive foodborne enteropathogen. After it is transmitted by fleas to warm-blooded animals and the needle part of the type III secretion system senses contact with a host cell, a signaling system influences five proteins to no longer inhibit secretion of the effector proteins that reorganize the host cell. One of these is YopN. However, while the frameshift product has a distinct impact on fitness, the reason is not understood despite extensive work on the complicated system involved (331). Polyamines are linked to controlling the type III secretion systems (333,334) and the prospect that polyamines could influence the frameshifting event leading to YopN-TyeA hybrid synthesis is considered tantalizing (331).