Title

The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.

Document Type

Article

Publication Date

9-3-2015

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.

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.