Control of alternative RNA splicing and gene expression by eukaryotic riboswitches

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Abstract
Riboswitches are elements present in some mRNAs that form alternative folded structures depending on the presence or absence of a small molecule ligand. These alternative structures determine whether protein is made from the mRNA. Here, a new way by which riboswitches affect protein expression, by affecting alternative splicing, is described. Bacteria make extensive use of riboswitches1,2 to sense metabolites and control gene expression, and typically do so by modulating premature transcription termination or translation initiation. The most widespread riboswitch class known in bacteria responds to the coenzyme thiamine pyrophosphate (TPP)3,4, which is a derivative of vitamin B1. Representatives of this class have also been identified5,6 in fungi and plants, where they are predicted5,7 to control messenger RNA splicing or processing. We examined three TPP riboswitches in the filamentous fungus Neurospora crassa, and found that one activates and two repress gene expression by controlling mRNA splicing. A detailed mechanism involving riboswitch-mediated base-pairing changes and alternative splicing control was elucidated for precursor NMT1 mRNAs, which code for a protein involved in TPP metabolism. These results demonstrate that eukaryotic cells employ metabolite-binding RNAs to regulate RNA splicing events that are important for the control of key biochemical processes.