Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 22, Issue 9, Pages 672-U45Publisher
NATURE PORTFOLIO
DOI: 10.1038/nsmb.3064
Keywords
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Funding
- US National Cancer Institute Cancer Center [P30 CA56036]
- US National Institutes of Health [GM100888, AI63432, AI083632, AI074805]
- University of Alabama at Birmingham Zebrafish Core
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Mycobacterium tuberculosis (Mtb) induces necrosis of infected cells to evade immune responses. Recently, we found that Mtb uses the protein CpnT to kill human macrophages by secreting its C-terminal domain, named tuberculosis necrotizing toxin (TNT), which induces necrosis by an unknown mechanism. Here we show that TNT gains access to the cytosol of Mtb-infected macrophages, where it hydrolyzes the essential coenzyme NAD(+). Expression or injection of a noncatalytic TNT mutant showed no cytotoxicity in macrophages or in zebrafish zygotes, respectively, thus demonstrating that the NAD(+) glycohydrolase activity is required for TNT-induced cell death. To prevent self-poisoning, Mtb produces an immunity factor for TNT (IFT) that binds TNT and inhibits its activity. The crystal structure of the TNT-IFT complex revealed a new NAD(+) glycohydrolase fold of TNT, the founding member of a toxin family widespread in pathogenic microorganisms.
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