Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 36, Pages E7450-E7459Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1707531114
Keywords
necroptosis; MLKL; disulfide bond; amyloid-like; polymer
Categories
Funding
- Welch Foundation [11827, 2T32GM008203-26A1, TL1TR1104, GM11104901A1]
- Virginia Murchison Linthicum Scholar in Medical Research
- Cancer Prevention and Research Institute of Texas (CPRIT) Scholar [R1222]
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Mixed-lineage kinase domain-like protein (MLKL) is essential for TNF-alpha-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 necrosul-fonamide 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.
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