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

PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors.

Chen D1,2, Tong J1,2, Yang L1,2, Wei L1,3, Stolz DB1,4, Yu J1,3, Zhang J5, Zhang L6,2.

Author information

1
UPMC Hillman Cancer Center, Pittsburgh, PA 15213.
2
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
3
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
4
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
5
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
6
UPMC Hillman Cancer Center, Pittsburgh, PA 15213; zhanglx@upmc.edu.

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

PMID:
29581256
PMCID:
PMC5899441
DOI:
10.1073/pnas.1717190115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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