A diguanylate cyclase acts as a cell division inhibitor in a two-step response to reductive and envelope stresses

Abstract

Bacteria use diverse nucleotide-based small molecules as second messengers to transduce various signals in their extra- and intracellular conditions, and to elicit appropriate cellular responses. The signaling molecule cyclic diguanylate (c-di-GMP) hasemerged as a ubiquitous nucleotide that controls a variety of cellular processes including motility, biofilm formation, virulence and cell differentiation. The intracellular levels of c-di-GMP are determined by the balance between its synthesis by diguanylate cyclases (DGCs) and degradation by phosphodiesterases (PDEs). Single bacterial species encode multiple DGC/PDEs harboring different sensory domains, surmised to integrate various input signals to regulate a common pool of c-di-GMP, which in turn regulates wideranging output processes. However, some c-di-GMP pathways appear to relay information selectively by spatial sequestration of particular DGC/PDEs. Here I discovered a new signaling pathway for YfiN, one of multiple DGCs found in E. coli and Salmonella. I show that YfiN interacts directly with components of the cell division machinery to inhibit division and growth, rather than acting through its product c-di-GMP. The DGC function of YfiN was known previously to be activated by a redox stress signal. My studies have revealed a second function, where redox-activated YfiN responds further to envelope stress by dynamically localizing to the division site and halting division. The unexpected bifunctionality of YfiN provides evidence that protein-protein interactions between c-di-GMP signaling components and their targets also confer signaling specificity, and reveals a new pathway for simultaneously inhibiting both cell division and cell growth in response to two stresses applied in a sequence.