MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis.
Proc Natl Acad Sci U S A
; 114(36): E7450-E7459, 2017 09 05.
Article
en En
| MEDLINE
| ID: mdl-28827318
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.
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Texto completo:
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Base de datos:
MEDLINE
Asunto principal:
Polímeros
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Proteínas Quinasas
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Apoptosis
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Disulfuros
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Amiloide
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Necrosis
Límite:
Animals
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Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2017
Tipo del documento:
Article