Biological events and molecular signaling following MLKL activation during necroptosis

Cell Cycle. 2017 Oct 2;16(19):1748-1760. doi: 10.1080/15384101.2017.1371889. Epub 2017 Aug 30.

Abstract

Necroptosis is a form of programmed necrotic cell death mediated by the kinase RIPK3 and its substrate MLKL. MLKL, which displays plasma membrane (PM) pore-forming activity upon phosphorylation, functions as the executioner during necroptosis. Thus, it was previously assumed that MLKL phosphorylation is the endpoint of the necroptotic signaling pathway. Here, we summarize several events that characterize the dying necroptotic cells after MLKL phosphorylation, including Ca2+ influx, phosphatidylserine (PS) externalization, PM repair by ESCRT-III activation, and the final compromise of PM integrity. These processes add several unexpected regulatory events downstream of MLKL signaling. We have also observed that CoCl2, which may mimic hypoxia, can induce necroptosis, which suggests that in vivo triggers of necroptosis might include a transient lack of O2.

Keywords: ESCRT; MLKL; Necroptosis; RIPK3; cell death; plasma membrane repair.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Calcium / metabolism
  • Cell Hypoxia
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cobalt / pharmacology
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • HT29 Cells
  • Humans
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Models, Biological
  • NIH 3T3 Cells
  • Necrosis / chemically induced
  • Necrosis / genetics
  • Necrosis / metabolism*
  • Phosphatidylserines / metabolism
  • Phosphorylation
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction / genetics*

Substances

  • Endosomal Sorting Complexes Required for Transport
  • Phosphatidylserines
  • Cobalt
  • MLKL protein, mouse
  • Protein Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • cobaltous chloride
  • Calcium