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

作者：Pajuelo David; Gonzalez Juarbe Norberto; Tak Uday; Sun Jim; Orihuela Carlos J; Niederweis Michael^*

来源：Cell Reports, 2018, 24(2): 429-440.

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-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.

• 出版日期2018-7-10