The Yersinia pseudotuberculosis Cpx envelope stress system contributes to transcriptional activation of rovM

Abstract

The Gram-negative enteropathogen Yersinia pseudotuberculosis possesses a number of regulatory systems that detect cell envelope damage caused by noxious extracytoplasmic stresses. The CpxA sensor kinase and CpxR response regulator two-component regulatory system is one such pathway. Active Cpx signalling upregulates various factors designed to repair and restore cell envelope integrity. Concomitantly, this pathway also down-regulates key determinants of virulence. In Yersinia, cpxA deletion accumulates high levels of phosphorylated CpxR (CpxR~P). Accumulated CpxR~P directly repressed rovA expression and this limited expression of virulence-associated processes. A second transcriptional regulator, RovM, also negatively regulates rovA expression in response to nutrient stress. Hence, this study aimed to determine if CpxR~P can influence rovA expression through control of RovM levels. We determined that the active CpxR~P isoform bound to the promoter of rovM and directly induced its expression, which naturally associated with a concurrent reduction in rovA expression. Site-directed mutagenesis of the CpxR~P binding sequence in the rovM promoter region desensitised rovM expression to CpxR~P. These data suggest that accumulated CpxR~P inversely manipulates the levels of two global transcriptional regulators, RovA and RovM, and this would be expected to have considerable influence on Yersinia pathophysiology and metabolism.

Bacterial virulence regulation through soluble peptidoglycan fragments sensing and response: knowledge gaps and therapeutic potential

“…The regulation capacity of CpxAR affects different virulence-related features, mostly depending on the species, including adherence to host tissues, resistance to serum, expression of toxin secretion systems, cellular invasion capacity, biofilm formation, and so on. But paradoxically, the CpxAR response seemingly exerts an activator effect on virulence factors in some species (Debnath et al 2013 , Bontemps et al 2015 , Li et al 2018 , Xie et al 2018 ), whereas its role is apparently repressor in others (Liu et al 2012 , Acosta et al 2015 , De la Cruz et al 2015 , 2016 , Thanikkal et al 2019 , Vogt et al 2019 ). These interesting particularities could be due to the ligand(s) that the CpxA sensor may bind, that could change depending on the scenario in which bacteria find themselves at each moment.…”

Maintaining Integrity Under Stress: Envelope Stress Response Regulation of Pathogenesis in Gram-Negative Bacteria

“…RovA, a global transcriptional regulator that activates the expression of invasin, is directly regulated by CpxR (Carlsson et al, 2007b). A further level of control was recently discovered when it was demonstrated that RovM, a regulator of RovA that represses its expression during nutrient limitation, was found to be directly CpxR-P regulated (Heroven and Dersch, 2006; Heroven et al, 2008; Thanikkal et al, 2019). Thus, RovA expression is not only modulated by CpxR at its own promoter, but also through CpxR upregulation of RovM.…”

Cpx-signalling facilitates Hms-dependent biofilm formation by Yersinia pseudotuberculosis

“…Follow-up work will need to establish whether these pathways work independently or through Cpx-signalling. We have already established existence of a CpxR-RovM-RovA regulatory cascade for the control of Yptb adhesion 49 , 50 and a CpxR-RcsA-RcsB regulatory cascade for the control of Yptb Ysc-Yop type III secretion 51 . Hence, it could be that these regulatory cascades may extend the influence of Cpx-signalling to fine-tuning biofilm development.…”

“…From earlier work on Yptb , the classical CpxAR two-component signalling system is involved in modulating the regulatory cascade outputs of RovA-RovM 49 , 50 and the Rcs phosphorelay system 51 . These couplings suggests that Cpx-signalling might also be involved in controlling aspects of biofilm development.…”