坏死性下垂
NAD+激酶
程序性细胞死亡
裂谷1
生物
细胞凋亡
肿瘤坏死因子α
结核分枝杆菌
巨噬细胞
Jurkat细胞
烟酰胺腺嘌呤二核苷酸
微生物学
细胞生物学
肺结核
免疫学
生物化学
酶
T细胞
医学
免疫系统
体外
病理
作者
David Pajuelo,Norberto González-Juarbe,Uday Tak,Jim Sun,Carlos J. Orihuela,Michael Niederweis
出处
期刊:Cell Reports
[Elsevier]
日期:2018-07-01
卷期号:24 (2): 429-440
被引量:131
标识
DOI:10.1016/j.celrep.2018.06.042
摘要
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.
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