I2BC Paris-Saclay

Researchers at I2BC have uncovered a family of small proteins that promotes spore formation in Clostridioides difficile, revealing how the bacterial messenger c-di-GMP controls this key process for the pathogen’s persistence and transmission.

Clostridioides difficile is a major intestinal pathogen responsible for severe antibiotic-associated infections. Its ability to form highly resistant spores is central to its success: spores can survive harsh conditions, facilitate transmission and contribute to the persistence of the pathogen. Sporulation is therefore a crucial step in the C. difficile life cycle, yet the mechanisms that determine when the bacterium enters this developmental program remain incompletely understood.
One important regulator of bacterial behavior is c-di-GMP, a signaling molecule that allows bacteria to adapt to changing environments. In C. difficile, c-di-GMP controls processes such as motility, adhesion and biofilm formation. High levels of c-di-GMP also inhibit sporulation, but the molecular mechanisms connecting this signal to spore formation have remained elusive. A distinctive feature of C. difficile is that many responses to c-di-GMP are mediated by riboswitches, regulatory RNA elements that sense this molecule and control gene expression.
Researchers of the I2BC show that the missing connection between c-di-GMP signaling and sporulation involves a previously uncharacterized family of very small, membrane-associated proteins. Several genes encoding these proteins are controlled by c-di-GMP-responsive riboswitches. Increasing the production of one family member strongly promotes the expression of sporulation genes and spore formation. Conversely, progressively deleting members of the family increasingly impairs sporulation, revealing that these proteins act collectively and can partially compensate for one another. High c-di-GMP levels repress their production, providing a molecular explanation for its inhibitory effect on sporulation. These findings uncover a new regulatory pathway connecting bacterial signaling to spore formation and reveal how tiny proteins can collectively control a key developmental decision in this important human pathogen.

More information : https://www.nature.com/articles/s41467-026-78452-6

Contact : Johann Peltier johann.peltier@i2bc.paris-saclay.fr

https://www.i2bc.paris-saclay.fr/regulatory-rnas-in-clostridia/