The QseC Adrenergic Signaling Cascade in Enterohemorrhagic E. coli (EHEC)

David T Hughes,Kaneyoshi Yamamoto,Marcie B Clarke,Vanessa Sperandio,David A Rasko,C Erec Stebbins

doi:10.1371/journal.ppat.1000553

Abstract

The ability to respond to stress is at the core of an organism's survival. The hormones epinephrine and norepinephrine play a central role in stress responses in mammals, which require the synchronized interaction of the whole neuroendocrine system. Mammalian adrenergic receptors are G-coupled protein receptors (GPCRs); bacteria, however, sense these hormones through histidine sensor kinases (HKs). HKs autophosphorylate in response to signals and transfer this phosphate to response regulators (RRs). Two bacterial adrenergic receptors have been identified in EHEC, QseC and QseE, with QseE being downstream of QseC in this signaling cascade. Here we mapped the QseC signaling cascade in the deadly pathogen enterohemorrhagic E. coli (EHEC), which exploits this signaling system to promote disease. Through QseC, EHEC activates expression of metabolic, virulence and stress response genes, synchronizing the cell response to these stress hormones. Coordination of these responses is achieved by QseC phosphorylating three of the thirty-two EHEC RRs. The QseB RR, which is QseC's cognate RR, activates the flagella regulon which controls bacteria motility and chemotaxis. The QseF RR, which is also phosphorylated by the QseE adrenergic sensor, coordinates expression of virulence genes involved in formation of lesions in the intestinal epithelia by EHEC, and the bacterial SOS stress response. The third RR, KdpE, controls potassium uptake, osmolarity, and also the formation of lesions in the intestine. Adrenergic regulation of bacterial gene expression shares several parallels with mammalian adrenergic signaling having profound effects in the whole organism. Understanding adrenergic regulation of a bacterial cell is a powerful approach for studying the underlying mechanisms of stress and cellular survival.

Highlights

The survival of an organism lies within its intrinsic ability to detect and efficiently respond to stress cues
Bacterial cells respond to the human stress hormones epinephrine and norepinephrine
These hormones are sensed by a bacterial receptor named QseC, which is a sensor kinase in the membrane that increases its autophosphorylation upon binding to these host signals

Summary

Introduction

The survival of an organism lies within its intrinsic ability to detect and efficiently respond to stress cues. Stress responses are generally termed ‘‘fight or flight’’ responses in higher animals, because they rely in the ability of an organism’s to assess whether its better chance of survival relies on facing or avoiding an environmental insult. In mammalian cells epinephrine and norepinephrine are recognized by GPCRs, which are membrane receptors coupled to heterotrimeric guanine-binding proteins (G-proteins). These proteins consist of three subunits a, b and c. G-proteins are divided in four families according to their association with effector proteins Three of these signaling pathways, Gas, Gai and Gaq, have been extensively studied, with Gas activating adenylate cyclase, Gai inhibiting adenylate cyclase, and Gaq activating phospholipoase C [1]

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