The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.
Document Type
Article
Publication Date
9-3-2015
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.
Recommended Citation
Sun, Jim; Siroy, Axel; Lokareddy, Ravi K; Speer, Alexander; Doornbos, Kathryn S; Cingolani, Gino; and Niederweis, Michael, "The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD." (2015). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 98.
https://jdc.jefferson.edu/bmpfp/98
PubMed ID
26237511
Comments
This article has been peer reviewed. It was published in: Nature Structural and Molecular Biology.
Volume 22, Issue 9, 3 September 2015, Pages 672-678.
The published version is available at DOI: 10.1038/nsmb.3064
Copyright © 2015 Nature America, Inc.