Is the Nickel-Dependent Urease Complex of Cryptococcus the Pathogen’s Achilles ’ Heel?

ABSTRACT The nitrogen-scavenging enzyme urease has been coopted in a variety of pathogenic organisms as a virulence factor, most notoriously to neutralize stomach acid and establish infection by the gastric pathogenHelicobacter pylori. The opportunis-tic fungal pathogen Cryptococcus neoformans also utilizes urease as a virulence factor, only in this case to invade the central ner-vous system (CNS) via the blood-brain barrier and cause life-threatening meningoencephalitis. A recent study [A. Singh, R. Panting, A. Varma, T. Saijo, K.Waldron, A. Jong, P. Ngamskulrungroj, Y. Chan, J. Rutherford, K. Kwon-Chung, mBio 4(3): e00220-13] genetically and biochemically characterizes the accessory proteins required for successful activation of the urease protein complex, including the essential nickel cofactor. The accessory proteins Ure4, Ure6, and Ure7 are all essential for urease function. Ure7 appears to combine the roles of two bacterial accessory proteins: it incorporates both the GTPase activity and nickel chaperone properties of UreE, a bacterial protein whose homolog is missing in the fungi. An accompanying nickel trans-porter, Nic1, is responsible for most, but not all, nickel uptake into the fungal cell. Mutants of the core urease protein Ure1, ac-cessory protein Ure7, and transporter Nic1 are all attenuated for invasion of the CNS of mice, and urease activity may directly affect integrity of the tight junction of the endothelial cells of the blood-brain barrier, the network of proteins that limits para-cellular permeability. This work highlights the potential of urease, its accessory proteins, and nickel transport as potential che-motherapeutic targets. Urea is a nitrogenous compound that plays important roles innitrogen metabolism and renal function and is frequentl