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.
Copyright © 2018 the Author(s). Published by PNAS.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Apoptosis*
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Cell Line, Tumor
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Cytosol / metabolism
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DNA / genetics
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DNA / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Glycoproteins / genetics
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Glycoproteins / metabolism*
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Humans
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mitochondria / genetics
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Mitochondria / metabolism
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Necrosis / genetics
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Necrosis / metabolism*
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Necrosis / physiopathology
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Phosphorylation
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA-Binding Proteins
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
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Signal Transduction
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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DNA-Binding Proteins
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Glycoproteins
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Membrane Proteins
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NF-kappa B
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PUMA protein, mouse
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Proto-Oncogene Proteins
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RNA-Binding Proteins
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STING1 protein, human
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Sting1 protein, mouse
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Proteins
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ZBP1 protein, human
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Zbp1 protein, mouse
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DNA
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MLKL protein, mouse
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Protein Kinases
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RIPK3 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk3 protein, mouse