Thursday, April 3, 2008

Microbe cheats death by misdirecting killer enzyme chaperone

Two million people die each year from tuberculosis and about a third of all humans are infected with the intracellular parasite responsible: Mycobacterium tuberculosis. This microbe overcomes the defenses of the macrophages it infects by inhibiting the fusion of phagosomes with lysosomes and avoiding the activity of reactive oxygen and nitrogen intermediates, including nitric oxide (NO). NO is extremely reactive and consequently short-lived, so the microbe misdirects the enzyme that produces NO, inducible NO synthase (iNOS), away from the phagosome. Davis and colleagues guessed that EBP50, a protein previously implicated in anchoring iNOS and other cellular proteins to the actin cytoskeleton, might be responsible.

They first showed that EBP50 is colocated with iNOS in the phagosomes of activated macrophages but less so after infection by M. tuberculosis. Reducing EBP50 with siRNA also reduced colocalization. Moreover, siRNA knockdown of EBP50 increased the viability of M. tuberculosis in infected macrophages, demonstrating its involvement in controlling this microbe (Figure, coronin is a control cytoskeletal chaperone that does not bind EBP50). However, since EBP50 is involved in many cellular processes, the specificity of the inhibition remains unproven.

Davis AS, Vergne I, Master SS, Kyei GB, Chua J, Deretic V. “Mechanism of Inducible Nitric Oxide Synthase Exclusion from Mycobacterial Phagosomes”. PLoS Pathog. 2007 Dec 7;3(12):e186

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