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

David Pajuelo, Norberto Gonzalez-Juarbe, Uday Tak, Jim Sun, Carlos J. Orihuela, Michael Niederweis

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)429-440
Number of pages12
JournalCell Reports
Volume24
Issue number2
DOIs
StatePublished - Jul 10 2018

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Keywords

  • MLKL
  • NAD
  • RIPK3
  • TNT
  • cell death
  • mitochondria
  • necroptosis
  • toxin
  • tuberculosis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Pajuelo, D., Gonzalez-Juarbe, N., Tak, U., Sun, J., Orihuela, C. J., & Niederweis, M. (2018). NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis. Cell Reports, 24(2), 429-440. https://doi.org/10.1016/j.celrep.2018.06.042