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Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):E7450-E7459. doi: 10.1073/pnas.1707531114. Epub 2017 Aug 21.

MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis.

Author information

1
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
2
School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330006, China.
3
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; zhigao.wang@utsouthwestern.edu.

Abstract

Mixed-lineage kinase domain-like protein (MLKL) is essential for TNF-α-induced necroptosis. How MLKL promotes cell death is still under debate. Here we report that MLKL forms SDS-resistant, disulfide bond-dependent polymers during necroptosis in both human and mouse cells. MLKL polymers are independent of receptor-interacting protein kinase 1 and 3 (RIPK1/RIPK3) fibers. Large MLKL polymers are more than 2 million Da and are resistant to proteinase K digestion. MLKL polymers are fibers 5 nm in diameter under electron microscopy. Furthermore, the recombinant N-terminal domain of MLKL forms amyloid-like fibers and binds Congo red dye. MLKL mutants that cannot form polymers also fail to induce necroptosis efficiently. Finally, the compound necrosulfonamide conjugates cysteine 86 of human MLKL and blocks MLKL polymer formation and subsequent cell death. These results demonstrate that disulfide bond-dependent, amyloid-like MLKL polymers are necessary and sufficient to induce necroptosis.

KEYWORDS:

MLKL; amyloid-like; disulfide bond; necroptosis; polymer

PMID:
28827318
PMCID:
PMC5594682
DOI:
10.1073/pnas.1707531114
[Indexed for MEDLINE]
Free PMC Article

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