HmsC, a periplasmic protein, controls biofilm formation via repression of HmsD, a diguanylate cyclase in Yersinia pestis

Abstract

Yersinia pestis, the cause of plague, forms a biofilm in the foregut of its flea vector to enhance transmission. Biofilm formation in Y. pestis is controlled by the intracellular levels of the second messenger molecule cyclic diguanylate (c-di-GMP). HmsT and Y3730, the two diguanylate cyclases (DGC) in Y. pestis, are responsible for the synthesis of c-di-GMP. Y3730, which we name here as HmsD, has little effect on in vitro biofilms, but has a major effect on biofilm formation in the flea. The mechanism by which HmsD plays differential roles in vivo and in vitro is not understood. In this study, we show that hmsD is part of a three-gene operon (y3729-31), which we designate as hmsCDE. Deletion of hmsC resulted in increased, hmsD-dependent biofilm formation, while deletion or overexpression of hmsE did not affect biofilm formation. Localization experiments suggest that HmsC resides in the periplasmic space. In addition, we provide evidence that HmsC might interact directly with the periplasmic domain of HmsD and cause the proteolysis of HmsD. We propose that HmsC senses the environmental signals, which in turn regulates HmsD, and controls the c-di-GMP synthesis and biofilm formation in Y. pestis.

The Yersinia pestis HmsCDE regulatory system is essential for blockage of the oriental rat flea (Xenopsylla cheopis), a classic plague vector

“…We demonstrated that HmsC (a YfiR orthologue) inhibits HmsD (a YfiN orthologue)‐dependent c‐di‐GMP synthesis and biofilm formation in vitro (Figs and ). This independently confirms the recently published findings of Ren and colleagues (). However, we went one step further to demonstrate that HmsE (a YfiB orthologue) counteracts HmsC to promote the activity of the DGC HmsD.…”

The Disulfide Bonding System Suppresses CsgD-Independent Cellulose Production in Escherichia coli

“…yfiRNB are in a single operon in E. coli, and YfiR and YfiN have similar activities in E. coli as those in P. aeruginosa (51)(52)(53)59). Previous work has also shown that the YfiN homolog AwsR controls Pseudomonas fluorescens cellulose and biofilm formation (60), and in Yersinia pestis, the YfiN and YfiR homologs, HmsD and HmsC, respectively, contribute to biofilm formation and the blockage of blood intake in the rat flea Xenopsylla cheopis (61,62). The inhibition of YfiN by YfiR can be overcome in P. aeruginosa via overexpression of the outer membrane protein YfiB, which sequesters YfiR away from YfiN (53).…”

“…4A and B). In Y. pestis, biofilm formation was only modestly affected by deletion or overexpression of the YfiB homolog HmsE (61,62). In UPEC strain CFT073, yfiR deletion leads to an increase in cellulose and curli production along with attenuation of bladder and kidney titers in a murine urinary tract infection (UTI) model (52).…”

Retracing the Evolutionary Path that Led to Flea-Borne Transmission of Yersinia pestis

“…Major differences occur, however, in genes that control intracellular levels of cyclic-di-GMP, a bacterial signaling molecule that induces biofilm development (Hennge, 2009). Y. pseudotuberculosis encodes three GGDEF-domain diguanylate cyclases (DGC) that synthesize c-di-GMP and three EAL-domain phosphodiesterases (PDE) that degrade it (Bobrov et al, 2011; Ren et al, 2013; Sun et al, 2011). Notably, two of the three PDE genes ( rtn and y3389 , hereafter referred to as PDE2 and PDE3) are pseudogenes in Y. pestis; only hmsP (PDE1) is functional (Figure 1).…”