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Science 12 December 2003:
Vol. 302. no. 5652, pp. 1963 - 1966
DOI: 10.1126/science.1091176
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Reports

The Proteasome of Mycobacterium tuberculosis Is Required for Resistance to Nitric Oxide

K. Heran Darwin,1 Sabine Ehrt,1 José-Carlos Gutierrez-Ramos,2 Nadine Weich,2 Carl F. Nathan1,3*

The production of nitric oxide and other reactive nitrogen intermediates (RNI) by macrophages helps to control infection by Mycobacterium tuberculosis (Mtb). However, the protection is imperfect and infection persists. To identify genes that Mtb requires to resist RNI, we screened 10,100 Mtb transposon mutants for hypersusceptibility to acidified nitrite. We found 12 mutants with insertions in seven genes representing six pathways, including the repair of DNA (uvrB) and the synthesis of a flavin cofactor (fbiC). Five mutants had insertions in proteasome-associated genes. An Mtb mutant deficient in a presumptive proteasomal adenosine triphosphatase was attenuated in mice, and exposure to proteasomal protease inhibitors markedly sensitized wild-type Mtb to RNI. Thus, the mycobacterial proteasome serves as a defense against oxidative or nitrosative stress.

1 Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
2 Millennium Pharmaceuticals, 75 Sidney Street, Cambridge, MA 02139, USA.
3 Programs in Immunology and Molecular Biology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.

* To whom correspondence should be addressed. E-mail: cnathan{at}med.cornell.edu

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