JB Accepts, published online ahead of print on 23 October 2009

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J. Bacteriol. doi:10.1128/JB.00848-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Cytoplasmic histidine kinase (HP0244) regulated assembly of urease with UreI, a channel for urea and its metabolites, CO₂, NH₃ and NH₄⁺, is necessary for acid survival of Helicobacter pylori.

David R Scott^*, Elizabeth A Marcus, Yi Wen, Siddarth Singh, Jing Feng, and George Sachs^*

Departments of Physiology, Medicine and Pediatrics, David Geffen School of Medicine at UCLA, 405 Hilgard Ave., Los Angeles, CA 90024; and the Veterans Administration Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073; and the Department of Internal Medicine, University of Iowa Hospitals and Clinics, Ames, IA

^* To whom correspondence should be addressed. Email: dscott{at}ucla.edu. gsachs{at}ucla.edu.

Helicobacter pylori colonizes the normal human stomach by maintaining both periplasmic and cytoplasmic pH close to neutral in gastric acidity. Urease activity, urea flux through the pH-gated urea channel, UreI, and periplasmic -carbonic anhydrase are essential for colonization. Exposure to pH 4.5 for up to 180 minutes activates total bacterial urease threefold. Within 30 minutes at pH 4.5, the urease structural subunits, UreA and UreB, and the Ni²⁺ insertion protein, UreE, are recruited to UreI at the inner membrane. Formation of this complex and urease activation depends on expression of the cytoplasmic sensor histidine kinase, HP0244. Its deletion abolishes urease activation and assembly, impairs cytoplasmic and periplasmic pH homeostasis and depolarizes the cells with a 7 log loss of survival at pH 2.5 even in 10mM urea. Associated with this assembly, UreI is able to transport NH₃, NH₄⁺ and CO₂ as shown by changes in cytoplasmic pH following exposure to NH₄Cl or CO₂.To be able to colonize the highly variable pH of the stomach, the organism expresses two pH-sensor histidine kinases, one, HP0165, responding to a moderate fall in periplasmic pH and the other, HP0244, responding to cytoplasmic acidification at more acidic medium pH. Assembly of a pH-regulatory complex of active urease with UreI provides an advantage for periplasmic buffering.