Regulation of mRNA Stability During Bacterial Stress Responses

Abstract

Bacteria have a remarkable ability to sense environmental changes, swiftly regulating their transcriptional and posttranscriptional machinery as a response. Under conditions that cause growth to slow or stop, bacteria typically stabilize their transcriptomes in what has been shown to be a conserved stress response. In recent years, diverse studies have elucidated many of the mechanisms underlying mRNA degradation, yet an understanding of the regulation of mRNA degradation under stress conditions remains elusive. In this review we discuss the diverse mechanisms that have been shown to affect mRNA stability in bacteria. While many of these mechanisms are transcript-specific, they provide insight into possible mechanisms of global mRNA stabilization. To that end, we have compiled information on how mRNA fate is affected by RNA secondary structures; interaction with ribosomes, RNA binding proteins, and small RNAs; RNA base modifications; the chemical nature of 5' ends; activity and concentration of RNases and other degradation proteins; mRNA and RNase localization; and the stringent response. We also provide an analysis of reported relationships between mRNA abundance and mRNA stability, and discuss the importance of stress-associated mRNA stabilization as a potential target for therapeutic development.

Keywords: bacteria; carbon starvation; hypoxia; mRNA degradation; mRNA stability; nutrient starvation; ribonucleic acid; stress response.

FIGURE 1

Environmental changes cause mRNA degradation rates to change in both global and gene-specific ways. Bacterial adaptation to many stressors, and other changes in environment, involve modulation of degradation rates of specific transcripts encoding proteins relevant to the changing conditions (top panel). Some stressors, particularly those causing severe energy stress, trigger global stabilization of the mRNA pool (bottom panel). These scenarios are not mutually exclusive; stressors that cause global transcriptome stabilization typically also cause gene-specific changes in relative degradation rates.

FIGURE 2

Bacterial degradosomes. The bacterial degradosome is scaffolded by an RNase such as RNase E in E. coli and RNase Y in B. subtilis. The RNase scaffolds have catalytic domains and natively disordered scaffold domains that bind other degradosome proteins. Typical degradosome components in both gram-positive and gram-negative bacteria are RNA helicases, carbon metabolism enzymes, and other RNases.

FIGURE 3

Common mechanisms that can protect mRNAs from degradation. (A) Degradosome localization can influence its RNA degradation activity. In E. coli, the degradosome is anchored to the cytoplasmic membrane via RNase E’s N-terminal domain, where it displays higher RNA processing activity in degradation foci. A cytoplasmic RNase E is less efficient in degradosome assembly and RNA processing. In B. subtilis, RNase Y is associated with the membrane and is more active when in smaller foci and less active when in larger foci. (B) RNA binding proteins can modulate mRNA degradation. Some of them, such as CsrA in γ-Proteobacteria, have regulatory roles as a response to environmental changes. (C) The chemical nature of mRNA 5′ ends can protect transcripts from degradation. These caps may vary depending on stress conditions. Nucleotide modifications in the bodies of transcripts have also been reported, but they have not been shown to alter mRNA stability. (D) RNA degradation depends on RNase accessibility to cleavage sites. Secondary structures that block cleavage sites can result in slower RNA degradation.

FIGURE 4

sRNAs can affect mRNA stability through multiple mechanisms. (A) sRNA binding can mask preferred RNase cleavage sites, thereby stabilizing transcripts. (B) sRNA binding can block ribosome access to Shine-Dalgarno sites, reducing translation and typically destabilizing transcripts. (C) In E. coli and some other gram-negative bacteria, sRNA-mRNA pairing is often mediated by Hfq, which typically leads to mRNA degradation.

FIGURE 5

Ribosome binding and stalling can alter mRNA degradation. In some cases, ribosome stalling can mask RNase cleavage sites, increasing the half-life of a transcript. Elements that prevent ribosome binding, such as translation initiation inhibitors, lead to shorter mRNA half-lives.

FIGURE 6

Polyadenylation regulates mRNA half-life. Stem-loops at mRNA 3′ ends block 3′–5′ exoribonucleases such as PNPase. PAP I, a poly(A) polymerase, can facilitate an exoribonuclease “grip” by synthesizing a poly(A) tail.

FIGURE 7

Relationships between mRNA abundance and mRNA decay rates. While some reports have shown a clear negative correlation between a transcript half-life and its abundance, a similar number of reports have found no correlation at all or a modest positive correlation, even for the same organism. Table 1 compiles transcriptome-wide analyses of mRNA decay in different organisms, techniques used, and information on the reported relationships between mRNA abundance and mRNA half-life.