DOI: 10.1126/science.1091176. The Proteasome of <i>Mycobacterium tuberculosis</i> Is Required for Resistance to Nitric Oxide

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

10.1126/science.1091176

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

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.

Bibliography

Darwin, K. H., Ehrt, S., Gutierrez-Ramos, J.-C., Weich, N., & Nathan, C. F. (2003). The Proteasome of Mycobacterium tuberculosis Is Required for Resistance to Nitric Oxide. Science, 302(5652), 1963â1966.

Authors 5

K. Heran Darwin (first)
Sabine Ehrt (additional)
José-Carlos Gutierrez-Ramos (additional)
Nadine Weich (additional)
Carl F. Nathan (additional)

References 23 Referenced 467

10.1146/annurev.immunol.15.1.323
U. E. Schaible, S. Sturgill-Koszycki, P. H. Schlesinger, D. G. Russell, J. Immunol.160, 1290 (1998). (10.4049/jimmunol.160.3.1290) / J. Immunol. (1998)
10.1084/jem.169.5.1543
10.1073/pnas.161295398
R. Long, B. Light, J. A. Talbot, Antimicrob. Agents Chemother.43, 403(1999). / Antimicrob. Agents Chemother. (1999)
C. Nathan, S. Ehrt, in In Tuberculosis, W. Rom, S. Garay, Eds. (Lippincott Williams and Wilkins, New York, ed. 2, 2003), pp. 215–235. / In Tuberculosis (2003)
10.1016/S0002-9440(10)65261-3
10.1164/rccm.2205016
T. Schon thesis Linköping Universitet Sweden (2002).
10.1073/pnas.94.10.5243
10.1016/S0140-6736(00)03493-0
10.1016/S1074-5521(01)00056-4
10.1016/S0300-9084(01)01250-0
10.1074/jbc.273.18.10857
10.1016/S0966-842X(98)01432-2
10.1038/31159
10.1006/jmbi.1997.1589
10.1038/35041081
10.1073/pnas.95.10.5752
10.1128/JB.180.20.5448-5453.1998
10.1046/j.1365-2958.2003.03425.x
10.1046/j.1365-2958.1997.4721837.x
We thank C. Sassetti and E. Rubin for providing the ϕMycoMarT7 transposon before its publication D. Ladant for the bacterial two-hybrid system D. Schappinger and D. Dou for polymerase chain reaction–screening the mutant library for prcBA mutants I. Orme for aerosol infection protocols H. T. Nguyen for histology M. Fuortes for calculations and photography and A. Darwin and A. Ding for review. Supported by NIH grants HL61241 AI055549 and T32 AI07621. The Department of Microbiology and Immunology acknowledges the support of the William Randolph Hearst Foundation. K.H.D. dedicates this work to the memory of Dr. Susan Valone.

Dates

Type	When
Created	21 years, 8 months ago (Dec. 11, 2003, 5:48 p.m.)
Deposited	1 year, 7 months ago (Jan. 9, 2024, 9:26 p.m.)
Indexed	2 weeks, 3 days ago (Aug. 12, 2025, 6:22 p.m.)
Issued	21 years, 8 months ago (Dec. 12, 2003)
Published	21 years, 8 months ago (Dec. 12, 2003)
Published Print	21 years, 8 months ago (Dec. 12, 2003)

Funders 0

None

BibTeX

@article{Darwin_2003, title={The Proteasome of Mycobacterium tuberculosis Is Required for Resistance to Nitric Oxide}, volume={302}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1091176}, DOI={10.1126/science.1091176}, number={5652}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Darwin, K. Heran and Ehrt, Sabine and Gutierrez-Ramos, José-Carlos and Weich, Nadine and Nathan, Carl F.}, year={2003}, month=dec, pages={1963–1966} }

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