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

Shuzhen Liu, Hua Liu, Andrea Johnston, Sarah Hanna-Addams, Eduardo Reynoso, Yougui Xiang, Zhigao Wang

Research output: Contribution to journalArticle

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E7450-E7459
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number36
DOIs
StatePublished - Sep 5 2017

Keywords

  • Amyloid-like
  • Disulfide bond
  • MLKL
  • Necroptosis
  • Polymer

ASJC Scopus subject areas

  • General

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