The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.

摘要: Mycobacterium tuberculosis (Mtb) induces necrosis of infected cells to evade immune responses. Recently, we found that Mtb uses the protein CpnT kill human macrophages by secreting its C-terminal domain, named necrotizing toxin (TNT), which an unknown mechanism. Here show TNT gains access cytosol Mtb-infected macrophages, where it hydrolyzes essential coenzyme NAD(+). Expression or injection a noncatalytic mutant showed no cytotoxicity in zebrafish zygotes, respectively, thus demonstrating NAD(+) glycohydrolase activity is required for TNT-induced cell death. To prevent self-poisoning, produces immunity factor (IFT) binds and inhibits activity. The crystal structure TNT-IFT complex revealed new fold TNT, founding member family widespread pathogenic microorganisms.