Post‐transcriptional Regulation and the Bacterial Response to Stress

Abstract

The molecular understanding of how organisms regulate their gene expression began in 1961 with the ground‐breaking work of Jacob and Monod, using bacterial genetics to explore the circuits for regulation of the lac operon and bacteriophage lambda lysogeny. In the intervening 50+ years, it has become clear that the lessons learned there, with variations, provide the basic mechanism for understanding transcriptional regulation in eukaryotes as well as prokaryotes. It has also become clear that regulating the initiation of transcription is only step one, and that cells regulate every possible step for gene expression, in myriad ways. We have found that different mechanisms of post‐transcriptional regulation collaborate to allow bacteria to mount a general stress response. In many bacteria, cells respond to nutrient starvation and/or various types of damage by inducing a response that provides cross‐resistance to a wide range of stresses. In E. coli, this stress response is mediated by expression of an alternative sigma factor, RpoS. Post‐transcriptional regulation increases expression of RpoS, highlighting the ways in which rapid responses to changes in the environment can be mediated post‐transcriptionally. Translation of RpoS requires the action of one or more small non‐coding RNAs (sRNAs), each of which positively regulates translation by opening up an inhibitory hairpin. These sRNAs are examples of a wide‐spread network of RNA regulators, akin to microRNAs in eukaryotes, that modulate mRNA stability and translation and are each induced in response to a different stress signal. The discovery of these sRNAs, when they are expressed, and what genes they regulate has uncovered unexpected regulatory networks in most bacteria. RpoS, once synthesized, binds to the core RNA polymerase to turn on the general stress regulon. However, when cells are growing rapidly (are not stressed), RpoS is rapidly degraded by the ATP‐dependent ClpXP protease; RpoS becomes stable when cells are starved or stressed. This protease, like the eukaryotic proteasome, consists of an ATPase and unfoldase, ClpX, through which substrates must be fed to the proteolytic chamber, ClpP. However, unlike eukaryotes, recognition of substrates in most bacteria does not depend upon ubiquitin tagging. For RpoS, an adaptor protein, RssB, delivers RpoS to the ATPase component of the protease. We have found that a set of anti‐adaptor proteins regulate RpoS stability via titration of the adaptor. Each anti‐adaptor is made in response to a different stress or starvation condition. Thus, as with the sRNAs, multiple signals can converge to induce RpoS via different antiadaptors, each leading to stabilization and thus increased activity of RpoS. The ability of bacteria like E. coli to adapt rapidly to multiple environments continues to provide new insights into regulation many years after the initial insights of Jacob and Monod.Support or Funding InformationThis research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.”