Iron–sulfur Rrf2 transcription factors: an emerging versatile platform for sensing stress

The widespread family of Rrf2 transcription factors has emerged as having prominent roles in diverse bacterial functions. These proteins share an overall common structure to sense and respond to stress signals. In many known cases, signaling occurs through iron–sulfur cluster cofactors. Recent research has highlighted distinct characteristics of individual family members that have enabled the Rrf2 family as a whole to sense a diverse array of stresses and subsequently alter gene expression to maintain homeostasis. Here, we review unique traits of four Rrf2 family members (IscR, NsrR, RisR, and RirA), which include iron–sulfur ligation schemes, stress-sensing mechanisms, protein conformation changes, and differential gene regulation, that allow these transcription factors to rapidly respond to environmental cues routinely encountered by bacteria.