Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death

Mixed lineage kinase domain-like protein (MLKL) was identified to function downstream of receptor interacting protein 3 (RIP3) in tumor necrosis factor-α (TNF)-induced necrosis (also called necroptosis). However, how MLKL functions to mediate necroptosis is unknown. By reconstitution of MLKL function in MLKL-knockout cells, we showed that the N-terminus of MLKL is required for its function in necroptosis. The oligomerization of MLKL in TNF-treated cells is essential for necroptosis, as artificially forcing MLKL together by using the hormone-binding domain (HBD*) triggers necroptosis. Notably, forcing together the N-terminal domain (ND) but not the C-terminal kinase domain of MLKL causes necroptosis. Further…

• NN
  National Natural Science Foundation of China

  Awards: 2014CB541804, 31221065, 31330047, 91029304, B12001
• XU
  Xiamen University
• HE
  Higher Education Discipline Innovation Project

  Award: B12001
• NH
  National High-tech Research and Development Program

  Award: 2012AA02A201
• NK
  National Key Research and Development Program of China

  Awards: 2014CB541804, 31221065, 2013CB944903, 91029304