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The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.

ABSTRACT: 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.

SUBMITTER: Sun J

PROVIDER: S-EPMC4560639 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.

Sun Jim J Siroy Axel A Lokareddy Ravi K RK Speer Alexander A Doornbos Kathryn S KS Cingolani Gino G Niederweis Michael M

Nature structural & molecular biology 20150803 9

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 cytotoxi ...[more]

PMID: 26237511

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