NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis

• Published in: Cell reports (Cambridge) Vol. 24; no. 2; pp. 429 - 440
• Main Authors: Pajuelo, David, Gonzalez-Juarbe, Norberto, Tak, Uday, Sun, Jim, Orihuela, Carlos J., Niederweis, Michael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.07.2018; Elsevier
• Subjects: Animals; Apoptosis - drug effects; Bacterial Toxins - toxicity; Biocatalysis - drug effects; cell death; Cytoprotection - drug effects; Humans; Jurkat Cells; Macrophages - drug effects; Macrophages - microbiology; Macrophages - pathology; Mice, Inbred C57BL; mitochondria; Mitochondria - drug effects; Mitochondria - pathology; MLKL; Models, Biological; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - metabolism; NAD; NAD - deficiency; NAD - metabolism; NAD+ Nucleosidase - metabolism; necroptosis; Necrosis; Niacinamide - pharmacology; Protein Kinases - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; RIPK3; THP-1 Cells; TNT; toxin; tuberculosis; Tumor Necrosis Factor-alpha - metabolism; NAD; RIPK3; MLKL; toxin; cell death; mitochondria; tuberculosis; TNT; necroptosis; NAD(+)
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.06.042

Mycobacterium tuberculosis (Mtb) kills infected macrophages by inhibiting apoptosis and promoting necrosis. The tuberculosis necrotizing toxin (TNT) is a secreted nicotinamide adenine dinucleotide (NAD+) glycohydrolase that induces necrosis in infected macrophages. Here, we show that NAD+ depletion by TNT activates RIPK3 and MLKL, key mediators of necroptosis. Notably, Mtb bypasses the canonical necroptosis pathway since neither TNF-α nor RIPK1 are required for macrophage death. Macrophage necroptosis is associated with depolarized mitochondria and impaired ATP synthesis, known hallmarks of Mtb-induced cell death. These results identify TNT as the main trigger of necroptosis in Mtb-infected macrophages. Surprisingly, NAD+ depletion itself was sufficient to trigger necroptosis in a RIPK3- and MLKL-dependent manner by inhibiting the NAD+ salvage pathway in THP-1 cells or by TNT expression in Jurkat T cells. These findings suggest avenues for host-directed therapies to treat tuberculosis and other infectious and age-related diseases in which NAD+ deficiency is a pathological factor. [Display omitted] •The NAD+ glycohydrolase TNT triggers necroptosis in macrophages infected by Mtb•NAD+ depletion below a critical threshold is sufficient to induce necroptosis•NAD+ replenishment protects cells from necroptosis and alleviates Mtb cytotoxicity Pajuelo et al. show that NAD+ hydrolysis by tuberculosis necrotizing toxin (TNT) induces necroptosis. NAD+ depletion alone is sufficient to activate RIPK3 and MLKL, bypassing canonical necroptosis initiation. These findings suggest ways to treat tuberculosis and other diseases in which NAD+ deficiency is a pathological factor.