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

Academic Article

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.
  • Published In

  • Cell Reports  Journal
  • Digital Object Identifier (doi)

    Author List

  • Pajuelo D; Gonzalez-Juarbe N; Tak U; Sun J; Orihuela CJ; Niederweis M
  • Start Page

  • 429
  • End Page

  • 440
  • Volume

  • 24
  • Issue

  • 2