PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors

Proc Natl Acad Sci U S A. 2018 Apr 10;115(15):3930-3935. doi: 10.1073/pnas.1717190115. Epub 2018 Mar 26.

Abstract

Necroptosis, a form of regulated necrotic cell death, is governed by RIP1/RIP3-mediated activation of MLKL. However, the signaling process leading to necroptotic death remains to be elucidated. In this study, we found that PUMA, a proapoptotic BH3-only Bcl-2 family member, is transcriptionally activated in an RIP3/MLKL-dependent manner following induction of necroptosis. The induction of PUMA, which is mediated by autocrine TNF-α and enhanced NF-κB activity, contributes to necroptotic death in RIP3-expressing cells with caspases inhibited. On induction, PUMA promotes the cytosolic release of mitochondrial DNA and activation of the DNA sensors DAI/Zbp1 and STING, leading to enhanced RIP3 and MLKL phosphorylation in a positive feedback loop. Furthermore, deletion of PUMA partially rescues necroptosis-mediated developmental defects in FADD-deficient embryos. Collectively, our results reveal a signal amplification mechanism mediated by PUMA and cytosolic DNA sensors that is involved in TNF-driven necroptotic death in vitro and in vivo.

Keywords: MLKL; NF-κB; PUMA; RIP3; necroptosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Apoptosis*
  • Cell Line, Tumor
  • Cytosol / metabolism
  • DNA / genetics
  • DNA / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Necrosis / genetics
  • Necrosis / metabolism*
  • Necrosis / physiopathology
  • Phosphorylation
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA-Binding Proteins
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • DNA-Binding Proteins
  • Glycoproteins
  • Membrane Proteins
  • NF-kappa B
  • PUMA protein, mouse
  • Proto-Oncogene Proteins
  • RNA-Binding Proteins
  • STING1 protein, human
  • Sting1 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • ZBP1 protein, human
  • Zbp1 protein, mouse
  • DNA
  • MLKL protein, mouse
  • Protein Kinases
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse