Collaborative Regulation ofEscherichia coliGlutamate-Dependent Acid Resistance by Two AraC-Like Regulators, GadX and GadW (YhiW)

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Abstract
An important feature ofEscherichia colipathogenesis is an ability to withstand extremely acidic environments of pH 2 or lower. This acid resistance property contributes to the low infectious dose of pathogenicE. colispecies. One very efficientE. coliacid resistance system encompasses two isoforms of glutamate decarboxylase (gadAandgadB) and a putative glutamate:γ-amino butyric acid (GABA) antiporter (gadC). The system is subject to complex controls that vary with growth media, growth phase, and growth pH. Previous work has revealed that the system is controlled by two sigma factors, two negative regulators (cyclic AMP receptor protein [CRP] and H-NS), and an AraC-like regulator called GadX. Earlier evidence suggested that the GadX protein acts both as a positive and negative regulator of thegadAandgadBCgenes depending on environmental conditions. New data clarify this finding, revealing a collaborative regulation between GadX and another AraC-like regulator called GadW (previously YhiW). GadX and GadW are DNA binding proteins that form homodimers in vivo and are 42% homologous to each other. GadX activates expression ofgadAandgadBCat any pH, while GadW inhibits GadX-dependent activation. Regulation ofgadAandgadBCby either regulator requires an upstream, 20-bp GAD box sequence. Northern blot analysis further indicates that GadW represses expression ofgadX. The results suggest a control circuit whereby GadW interacts with both thegadAandgadXpromoters. GadW clearly repressesgadXand, in situations where GadX is missing, activatesgadAandgadBC.GadX, however, activates onlygadAandgadBCexpression. CRP also repressesgadXexpression. It does this primarily by repressing production of sigma S, the sigma factor responsible forgadXexpression. In fact, the acid induction ofgadAandgadBCobserved when rich-medium cultures enter stationary phase corresponds to the acid induction of sigma S production. These complex control circuits impose tight rein over expression of thegadAandgadBCsystem yet provide flexibility for inducing acid resistance under many conditions that presage acid stress.

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