The RgaS-RgaR two-component system promotes Clostridioides difficile sporulation through a small RNA and the Agr1 system

• Type of Material: Article
• Authors: Adrianne Edwards, Emory University; Shonna McBride, Emory University
• Language: English
• Date: 2023-10-16
• Publisher: PLOS
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Edwards, McBride
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1371%2Fjournal.pgen.1010841
• Title of Journal or Parent Work: PLOS Genetics
• Volume: 19
• Issue: 10
• Start Page: e1010841
• Grant/Funding Information: This research was supported by the U.S. National Institutes of Health through research grants AI116933 and AI156052 to S.M.M.
• Keywords: Spo0A; agrB1D1; Clostridioides difficile
• Research Categories: Biology, Genetics

Abstract

The ability to form a dormant spore is essential for the survival of the anaerobic pathogen, Clostridioides difficile, outside of the mammalian gastrointestinal tract. The initiation of sporulation is governed by the master regulator of sporulation, Spo0A, which is activated by phosphorylation. Multiple sporulation factors control Spo0A phosphorylation; however, this regulatory pathway is not well defined in C. difficile. We discovered that RgaS and RgaR, a conserved orphan histidine kinase and orphan response regulator, function together as a cognate two-component regulatory system to directly activate transcription of several genes. One of these targets, agrB1D1, encodes gene products that synthesize and export a small quorum-sensing peptide, AgrD1, which positively influences expression of early sporulation genes. Another target, a small regulatory RNA now known as SpoZ, impacts later stages of sporulation through a small hypothetical protein and an additional, unknown regulatory mechanism(s). Unlike Agr systems in many organisms, AgrD1 does not activate the RgaS-RgaR two-component system, and thus, is not responsible for autoregulating its own production. Altogether, we demonstrate that C. difficile utilizes a conserved two-component system that is uncoupled from quorum-sensing to promote sporulation through two distinct regulatory pathways.