Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 12 December 2003:
Vol. 302. no. 5652, pp. 1963 - 1966
DOI: 10.1126/science.1091176
Prev | Table of Contents | Next

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

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
CD23 Mediates Antimycobacterial Activity of Human Macrophages.
M. D. Mossalayi, I. Vouldoukis, M. Mamani-Matsuda, T. Kauss, J. Guillon, J. Maugein, D. Moynet, J. Rambert, V. Desplat, D. Mazier, et al. (2009)
Infect. Immun. 77, 5537-5542
   Abstract »    Full Text »    PDF »
Lipoprotein Processing Is Essential for Resistance of Mycobacterium tuberculosis to Malachite Green.
N. Banaei, E. Z. Kincaid, S.-Y. G. Lin, E. Desmond, W. R. Jacobs Jr., and J. D. Ernst (2009)
Antimicrob. Agents Chemother. 53, 3799-3802
   Abstract »    Full Text »    PDF »
Conversion of NO2 to NO by reduced coenzyme F420 protects mycobacteria from nitrosative damage.
E. Purwantini and B. Mukhopadhyay (2009)
PNAS 106, 6333-6338
   Abstract »    Full Text »    PDF »
Proteasomal Protein Degradation in Mycobacteria Is Dependent upon a Prokaryotic Ubiquitin-like Protein.
K. E. Burns, W.-T. Liu, H. I. M. Boshoff, P. C. Dorrestein, and C. E. Barry 3rd (2009)
J. Biol. Chem. 284, 3069-3075
   Abstract »    Full Text »    PDF »
Distinct Specificities of Mycobacterium tuberculosis and Mammalian Proteasomes for N-Acetyl Tripeptide Substrates.
G. Lin, C. Tsu, L. Dick, X. K. Zhou, and C. Nathan (2008)
J. Biol. Chem. 283, 34423-34431
   Abstract »    Full Text »    PDF »
PA-824 Kills Nonreplicating Mycobacterium tuberculosis by Intracellular NO Release.
R. Singh, U. Manjunatha, H. I. M. Boshoff, Y. H. Ha, P. Niyomrattanakit, R. Ledwidge, C. S. Dowd, I. Y. Lee, P. Kim, L. Zhang, et al. (2008)
Science 322, 1392-1395
   Abstract »    Full Text »    PDF »
Regulation of the SigH stress response regulon by an essential protein kinase in Mycobacterium tuberculosis.
S. T. Park, C.-M. Kang, and R. N. Husson (2008)
PNAS 105, 13105-13110
   Abstract »    Full Text »    PDF »
Important role of the nucleotide excision repair pathway in Mycobacterium smegmatis in conferring protection against commonly encountered DNA-damaging agents.
K. Kurthkoti, P. Kumar, R. Jain, and U. Varshney (2008)
Microbiology 154, 2776-2785
   Abstract »    Full Text »    PDF »
Crystal Structures of F420-dependent Glucose-6-phosphate Dehydrogenase FGD1 Involved in the Activation of the Anti-tuberculosis Drug Candidate PA-824 Reveal the Basis of Coenzyme and Substrate Binding.
G. Bashiri, C. J. Squire, N. J. Moreland, and E. N. Baker (2008)
J. Biol. Chem. 283, 17531-17541
   Abstract »    Full Text »    PDF »
Mycobacterial persistence requires the utilization of host cholesterol.
A. K. Pandey and C. M. Sassetti (2008)
PNAS 105, 4376-4380
   Abstract »    Full Text »    PDF »
Genetic and Proteomic Analyses of a Proteasome-Activating Nucleotidase A Mutant of the Haloarchaeon Haloferax volcanii.
P. A. Kirkland, M. A. Gil, I. M. Karadzic, and J. A. Maupin-Furlow (2008)
J. Bacteriol. 190, 193-205
   Abstract »    Full Text »    PDF »
Mycobacterium smegmatis mc2 155 fbiC and MSMEG_2392 are involved in triphenylmethane dye decolorization and coenzyme F420 biosynthesis.
D. Guerra-Lopez, L. Daniels, and M. Rawat (2007)
Microbiology 153, 2724-2732
   Abstract »    Full Text »    PDF »
A Genetic Screen for Mycobacterium tuberculosis Mutants Defective for Phagosome Maturation Arrest Identifies Components of the ESX-1 Secretion System.
J. A. MacGurn and J. S. Cox (2007)
Infect. Immun. 75, 2668-2678
   Abstract »    Full Text »    PDF »
Genome-Wide Identification of Francisella tularensis Virulence Determinants.
J. Su, J. Yang, D. Zhao, T. H. Kawula, J. A. Banas, and J.-R. Zhang (2007)
Infect. Immun. 75, 3089-3101
   Abstract »    Full Text »    PDF »
Characterization of the Proteasome Accessory Factor (paf) Operon in Mycobacterium tuberculosis.
R. A. Festa, M. J. Pearce, and K. H. Darwin (2007)
J. Bacteriol. 189, 3044-3050
   Abstract »    Full Text »    PDF »
Characterization of the Helicase Activity and Substrate Specificity of Mycobacterium tuberculosis UvrD.
E. Curti, S. J. Smerdon, and E. O. Davis (2007)
J. Bacteriol. 189, 1542-1555
   Abstract »    Full Text »    PDF »
A Mycobacterium marinum mel2 Mutant Is Defective for Growth in Macrophages That Produce Reactive Oxygen and Reactive Nitrogen Species.
S. Subbian, P. K. Mehta, S. L. G. Cirillo, L. E. Bermudez, and J. D. Cirillo (2007)
Infect. Immun. 75, 127-134
   Abstract »    Full Text »    PDF »
Dihydrolipoamide Acyltransferase Is Critical for Mycobacterium tuberculosis Pathogenesis.
S. Shi and S. Ehrt (2006)
Infect. Immun. 74, 56-63
   Abstract »    Full Text »    PDF »
Identification of Histoplasma capsulatum Transcripts Induced in Response to Reactive Nitrogen Species.
M. P. Nittler, D. Hocking-Murray, C. K. Foo, and A. Sil (2005)
Mol. Biol. Cell 16, 4792-4813
   Abstract »    Full Text »    PDF »
Inactivation of the 20S proteasome in Streptomyces lividans and its influence on the production of heterologous proteins.
B. Hong, L. Wang, E. Lammertyn, N. Geukens, L. Van Mellaert, Y. Li, and J. Anne (2005)
Microbiology 151, 3137-3145
   Abstract »    Full Text »    PDF »
Role for Nucleotide Excision Repair in Virulence of Mycobacterium tuberculosis.
K. H. Darwin and C. F. Nathan (2005)
Infect. Immun. 73, 4581-4587
   Abstract »    Full Text »    PDF »
S-nitroso proteome of Mycobacterium tuberculosis: Enzymes of intermediary metabolism and antioxidant defense.
K. Y. Rhee, H. Erdjument-Bromage, P. Tempst, and C. F. Nathan (2005)
PNAS 102, 467-472
   Abstract »    Full Text »    PDF »
Identification of Mycobacterium tuberculosis Counterimmune (cim) Mutants in Immunodeficient Mice by Differential Screening.
K. B. Hisert, M. A. Kirksey, J. E. Gomez, A. O. Sousa, J. S. Cox, W. R. Jacobs Jr., C. F. Nathan, and J. D. McKinney (2004)
Infect. Immun. 72, 5315-5321
   Abstract »    Full Text »    PDF »
Mechanisms of Resistance to Oxidative and Nitrosative Stress: Implications for Fungal Survival in Mammalian Hosts.
T. A. Missall, J. K. Lodge, and J. E. McEwen (2004)
Eukaryot. Cell 3, 835-846
   Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)