Na+ riboswitches regulate genes for diverse physiological processes in bacteria

Abstract

Organisms presumably have mechanisms to monitor and physiologically adapt to changes in cellular Na+ concentrations. Only a single bacterial protein has previously been demonstrated to selectively sense Na+ and regulate gene expression. Here we report a riboswitch class, previously called the ‘DUF1646 motif’, whose members selectively sense Na+ and regulate the expression of genes relevant to sodium biology. Many proteins encoded by Na+-riboswitch-regulated genes are annotated as metal ion transporters, whereas others are involved in mitigating osmotic stress or harnessing Na+ gradients for ATP production. Na+ riboswitches exhibit dissociation constants in the low mM range, and strongly reject all other alkali and alkaline earth ions. Likewise, only Na+ triggers riboswitch-mediated transcription and gene expression changes. These findings reveal that some bacteria use Na+ riboswitches to monitor, adjust and exploit Na+ concentrations and gradients, and in some instances collaborate with c-di-AMP riboswitches to coordinate gene expression during osmotic stress.

The Biochemical Landscape of Riboswitch Ligands

“…A growing list of elemental ions are known to be sensed by various riboswitch classes. The Na + -I riboswitch 43 class is known to regulate Na + transporters, which could allow cells to avoid the accumulation of toxic levels of this cation. As also noted earlier, some representatives of this riboswitch class regulate the expression of ATP synthase components that exploit a Na + gradient to generate energy in the form of phosphoanhydride linkages.…”

“…As also noted earlier, some representatives of this riboswitch class regulate the expression of ATP synthase components that exploit a Na + gradient to generate energy in the form of phosphoanhydride linkages. In rare instances, 43 a Na + -I riboswitch is found in tandem with a riboswitch for the signaling molecule cyclic diadenosine phosphate (c-di-AMP). 77 A general role for this signaling molecule is to regulate processes involved in overcoming osmotic stress.…”

“…The closest any known riboswitch class comes to proton management is found with Na + -I riboswitches. 43 These riboswitches sense Na + as the name indicates and frequently regulate Na + /H + antiporters that operate best under alkaline conditions. This permits cells to exploit a Na + gradient to import H + when cells are living in alkaline environments, thereby maintaining the desired near-neutral pH inside cells.…”

“…Two riboswitch classes do modulate genes that can affect cellular phosphate levels, although their major roles are categorized differently. Na + -I riboswitches 43 occasionally regulate the expression of genes for ATP synthase complexes powered by a Na + gradient. The action of ATP synthase is to couple inorganic phosphate to ADP to generate ATP.…”

A Riboswitch-Driven Era of New Antibacterials

“…They are classified according to their cognate ligand aptamer domain which possesses highly selective binding sites for ligands and is highly conserved among different species [ 6 ]. Their natural ligands include coenzymes (flavin mononucleotide (FMN), thiamin pyrophosphate (TPP), coenzyme B12); nucleobases and their derivatives (adenine, guanine, c-di-GMP, c-di-AMP, pre-queuosine (preQ1)); cations such as Mg 2+ and Mn 2+ , Ni 2+ /Co 2+ and Na + and anions such as fluoride, amino acids and derivatives (lysine, glycine, S-adenosyl methionine (SAM), S-adenosyl homocysteine (SAH)); carbohydrates (glucosamine-6-phosphate (GlcN6P)); and guanidine [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. T-box riboswitches represent a distinct class of riboswitches whose cognate ligand is the tRNA molecule, which interact through a codon–anticodon-like manner, and are involved in amino-acid metabolism [ 23 , 24 , 25 ].…”