Protein acylation by saturated very long chain fatty acids and endocytosis are involved in necroptosis

Cell Chem Biol. 2021 Sep 16;28(9):1298-1309.e7. doi: 10.1016/j.chembiol.2021.03.012. Epub 2021 Apr 12.


Necroptosis is a form of cell death characterized by receptor-interacting protein kinase activity and plasma membrane permeabilization via mixed-lineage kinase-like protein (MLKL). This permeabilization is responsible for the inflammatory properties of necroptosis. We previously showed that very long chain fatty acids (VLCFAs) are functionally involved in necroptosis, potentially through protein fatty acylation. Here, we define the scope of protein acylation by saturated VLCFAs during necroptosis. We show that MLKL and phosphoMLKL, key for membrane permeabilization, are exclusively acylated during necroptosis. Reducing the levels of VLCFAs decreases their membrane recruitment, suggesting that acylation by VLCFAs contributes to their membrane localization. Acylation of phosphoMLKL occurs downstream of phosphorylation and oligomerization and appears to be, in part, mediated by ZDHHC5 (a palmitoyl transferase). We also show that disruption of endosomal trafficking increases cell viability during necroptosis, possibly by preventing recruitment, or removal, of phosphoMLKL from the plasma membrane.

Keywords: VLCFA; ZDHHC5; endocytosis; lipids; necroptosis; programmed cell death; protein acylation; vesicular trafficking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acylation / drug effects
  • Acyltransferases / antagonists & inhibitors*
  • Acyltransferases / metabolism
  • Endocytosis / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Fatty Acids / chemistry
  • Fatty Acids / pharmacology*
  • HT29 Cells
  • Humans
  • Necroptosis / drug effects
  • Tumor Cells, Cultured


  • Enzyme Inhibitors
  • Fatty Acids
  • Acyltransferases
  • ZDHHC5 protein, human