Bacterial Iron Homeostasis Regulation by sRNAs

Abstract

While iron is essential to sustain growth, its excess can be detrimental to the cell by generating highly toxic reactive oxygen species. Regulation of iron homeostasis thus plays a vital role in almost all living organisms. During the last 15 years, the small RNA (sRNA) RyhB has been shown to be a key actor of iron homeostasis regulation in bacteria. Through multiple molecular mechanisms, RyhB represses expendable iron-utilizing proteins, promotes siderophore production, and coordinates Fe-S cluster cofactor biogenesis, thereby establishing a so-called iron-sparing response. In this review, we will summarize knowledge on how sRNAs control iron homeostasis mainly through studies on RyhB in Escherichia coli. The parallel roles and modes of action of other sRNAs in different bacteria will also be described. Finally, we will discuss what questions remain to be answered concerning this important stress response regulation by sRNAs.

FIGURE 1

RyhB regulatory mechanisms. (A) RyhB represses expression of multiple mRNAs by inhibiting translation initiation and inducing mRNA degradation. RyhB base-pairing blocks ribosome attachment to the RBS. Consequently, the mRNA is degraded by RNase E recruitment at sites that can be distant from the base-pairing region. (B) RyhB promotes the degradation of the iscRSUA transcript by base-pairing to the translation initiation region of iscS while the 5′ part of the mRNA, encoding iscR, remains stable and is translated. (C) RyhB positively regulates shiA expression by opening a stem-loop structure that otherwise inhibits ribosome attachment to the RBS. (D) RyhB activates translation of cirA by displacing Hfq, which otherwise blocks ribosome attachment. (E) RyhB’s activity can be modulated thanks to the 3′ external transcribed spacer of the glyW-cysE-leuZ tRNA (in purple).

FIGURE 2

The iron-sparing response established by RyhB. Under iron-replete conditions, Fur-Fe²⁺ represses ryhB expression. During iron starvation, Fur repression is abolished and RyhB is rapidly expressed. RyhB mediates an Fe-sparing response through three mechanisms: (A) RyhB represses the expression of mRNAs coding for iron-using proteins; (B) RyhB, together with IscR, orchestrates Fe-S biogenesis systems through regulation of the Isc machinery and erpA expression; and (C) RyhB promotes Fe uptake via the upregulation of shiA and cirA and repression of the cysE gene, which leads to serine accumulation used for enterobactin production.