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- Title
The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.
- Authors
Sun, Jim; Siroy, Axel; Lokareddy, Ravi K; Speer, Alexander; Doornbos, Kathryn S; Cingolani, Gino; Niederweis, Michael
- 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.
- Subjects
MYCOBACTERIUM tuberculosis; KILLER cells; MYCOBACTERIAL diseases; CHEST diseases; RETICULO-endothelial system
- Publication
Nature Structural & Molecular Biology, 2015, Vol 22, Issue 9, p672
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb.3064