| First Author | Pajuelo D | Year | 2018 |
| Journal | Cell Rep | Volume | 24 |
| Issue | 2 | Pages | 429-440 |
| PubMed ID | 29996103 | Mgi Jnum | J:271251 |
| Mgi Id | MGI:6279130 | Doi | 10.1016/j.celrep.2018.06.042 |
| Citation | Pajuelo D, et al. (2018) NAD(+) Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis. Cell Rep 24(2):429-440 |
| abstractText | 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-alpha 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. |
