StaphylococcalsRNA IsrR down-regulates methylthiotransferase MiaB under iron-deficient conditions

Abstract

ABSTRACTStaphylococcus aureusis a major contributor to bacterial-associated mortality, owing to its exceptional adaptability across diverse environments. Iron, vital for most organisms, poses toxicity risks in excess. To manage iron,S. aureus, like many pathogens, employs intricate systems. We have recently identified IsrR as a key regulatory RNA induced during iron starvation. Its role is to curtail the synthesis of non-essential iron-containing proteins under iron-depleted conditions. In this study, we unveil IsrR’s regulatory action on MiaB, an enzyme responsible for methylthio group addition to specific sites on transfer RNAs (tRNAs). We use predictive tools and reporter fusion assays to demonstrate IsrR’s binding to the Shine-Dalgarno sequence ofmiaBRNA, thereby impeding its translation. The effectiveness of IsrR hinges on the integrity of a specific C-rich region. As MiaB is non-essential and contains two [4Fe-4S] clusters, IsrR induction spares iron by downregulatingmiaB. This likely enhancesS. aureusfitness and aids in navigating the host’s nutritional immune defenses.IMPORTANCEIn numerous biotopes, including those found within an infected host, bacteria confront the challenge of iron deficiency. They employ various strategies to adapt to this scarcity of nutrients, one of which involves the regulation of iron-containing proteins through the action of small regulatory RNAs. In our study, we demonstrate how IsrR, a small RNA fromS. aureus, inhibits the translation of MiaB, a tRNA-modifying enzyme containing [Fe-S] clusters. Through this illustration, we shed light on a novel substrate for a small RNA sparing iron, thereby unveiling a way by which bacteria conserve their iron resource.