Turning riboswitches loose.

Riboswitches are mRNA-based modules that control gene expression through direct RNA-ligand interactions.[1) In most cases, the regulatory ligands are metabolites that act on their own biosynthesis genes through feedback regulation. Since their discovery by Breaker and co-workers in 2002, nucleobases, amino acids, cofactors, as well as the amino sugar glucosamine-6-phosphate have been described to trigger changes in gene expression by binding to riboswitches.(1) It became apparent that such protein-free regulation mechanisms are frequently found in bacteria with some examples such as thiamine pyrophosphate-dependent switches that even operate in plants and fungi. Riboswitches mostly operate through a common mechanism: ligand binding to an aptamer domain triggers a rearrangement in the 5'-untranslated region of an mRNA at which bacterial riboswitches usually are located. This event results in a structural rearrangement of the so-called expression platform, and provokes changes in transcription termination or initiation of translation. A different mechanism has been described in case of the glms-riboswitch in which glucosamine-6-phosphate acts as a cofactor and triggers scission of the respective mRNA through the action of a phosphodiestercleaving ribozyme. The described riboswitches are typical examples of in cisacting regulatory mechanisms; this means that the riboswitch exclusively controls the expression of the riboswitch-containing mRNA. On the other hand, several examples of in transacting small regulatory RNAs (so-called sRNAs) have been described in bacteria.[2) A subclass of sRNAs acts in trans through base-pairing to mRNAs that contain complementary sequences. In a recent report (ossart, Johansson and co-workers described for the first time that riboswitches formerly identified to be regulated by the cofactor S-adenosylmethionine (SAM)[3) also act on other mRNAs in the pathogen Listeria monocytogenes.l) L. monocytogenes is a Gram-positive bacterium that causes a food-borne infection called listeriosis. Over 40 different noncoding RNAs have been described in L. monocytogenes previously.[S) Among them, SAM-dependent riboswitches are found in mRNAs that code for methionine and cysteine metabolism and uptake. They act by terminating transcription upon SAM binding, see Figure 1 A. Surprisingly, two of these SAM riboswitches (SreA and SreB) were found to influence the expression of several other genes. The influence on one of these genes, the virulence factor PrfA, was studied in more detail and found to be inhibited in trans, presumably through an an-