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The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide.

TitleThe proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide.
Publication TypeJournal Article
Year of Publication2003
AuthorsK Darwin H, Ehrt S, Gutierrez-Ramos J-C, Weich N, Nathan CF
JournalScience
Volume302
Issue5652
Pagination1963-6
Date Published2003 Dec 12
ISSN1095-9203
KeywordsAdenosine Triphosphatases, Amide Synthases, Animals, Antitubercular Agents, Bacterial Proteins, Carrier Proteins, Colony Count, Microbial, Cysteine Endopeptidases, DNA Transposable Elements, Genes, Bacterial, Genetic Complementation Test, Hydrogen Peroxide, Hydrogen-Ion Concentration, Macrophages, Mice, Mice, Inbred C57BL, Microbial Sensitivity Tests, Multienzyme Complexes, Mutation, Mycobacterium tuberculosis, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Nitrites, Oxidative Stress, Protease Inhibitors, Proteasome Endopeptidase Complex, Tuberculosis, Virulence
Abstract

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.

DOI10.1126/science.1091176
Alternate JournalScience
PubMed ID14671303
Grant ListAI055549 / AI / NIAID NIH HHS / United States
HL61241 / HL / NHLBI NIH HHS / United States
T32 AI07621 / AI / NIAID NIH HHS / United States

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