The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide.
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.
Darwin
K Heran
KH
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Ehrt
Sabine
S
Gutierrez-Ramos
José-Carlos
JC
Weich
Nadine
N
Nathan
Carl F
CF
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019732:Amide Synthases; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015169:Colony Count, Microbial; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004251:DNA Transposable Elements; D005798:Genes, Bacterial; D005816:Genetic Complementation Test; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000494:pharmacology; D018384:Oxidative Stress; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D014376:Tuberculosis / Q000382:microbiology; D014774:Virulence
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D004251:DNA Transposable Elements; D009097:Multienzyme Complexes; D009573:Nitrites; D011480:Protease Inhibitors; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C479920:Mpa protein, Mycobacterium tuberculosis; D019732:Amide Synthases; C479921:Paf protein, Mycobacterium tuberculosis