NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis
Summary: 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+ d...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-07-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718309525 |
| _version_ | 1828515010721087488 |
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| author | David Pajuelo Norberto Gonzalez-Juarbe Uday Tak Jim Sun Carlos J. Orihuela Michael Niederweis |
| author_facet | David Pajuelo Norberto Gonzalez-Juarbe Uday Tak Jim Sun Carlos J. Orihuela Michael Niederweis |
| author_sort | David Pajuelo |
| collection | DOAJ |
| description | Summary: 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. : 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. Keywords: tuberculosis, necroptosis, RIPK3, MLKL, NAD+, toxin, TNT, mitochondria, cell death |
| first_indexed | 2024-12-11T18:07:32Z |
| format | Article |
| id | doaj.art-e06a2155e4f043beb3799f3b5013d544 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T18:07:32Z |
| publishDate | 2018-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-e06a2155e4f043beb3799f3b5013d5442022-12-22T00:55:41ZengElsevierCell Reports2211-12472018-07-01242429440NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosisDavid Pajuelo0Norberto Gonzalez-Juarbe1Uday Tak2Jim Sun3Carlos J. Orihuela4Michael Niederweis5Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Corresponding authorSummary: 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. : 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. Keywords: tuberculosis, necroptosis, RIPK3, MLKL, NAD+, toxin, TNT, mitochondria, cell deathhttp://www.sciencedirect.com/science/article/pii/S2211124718309525 |
| spellingShingle | David Pajuelo Norberto Gonzalez-Juarbe Uday Tak Jim Sun Carlos J. Orihuela Michael Niederweis NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis Cell Reports |
| title | NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis |
| title_full | NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis |
| title_fullStr | NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis |
| title_full_unstemmed | NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis |
| title_short | NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis |
| title_sort | nad depletion triggers macrophage necroptosis a cell death pathway exploited by mycobacterium tuberculosis |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718309525 |
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