SUMO-Modified FADD Recruits Cytosolic Drp1 and Caspase-10 to Mitochondria for Regulated Necrosis

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Evaluation of Caspase Activation to Assess Innate Immune Cell Death
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Seon-Guk Choi1, Hyunjoo Kim1, Eun Il Jeong1

  • 1Department of Biological Science, Seoul National University, Seoul, South Korea.

Molecular and Cellular Biology
|November 2, 2016
PubMed

Insights

Fas-associated protein with death domain (FADD) is SUMOylated during necrosis, promoting mitochondrial fragmentation via dynamin-related protein 1 (Drp1) and caspase-10. This reveals a new mechanism for regulated necrosis in calcium overload and ischemic injury.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Fas-associated protein with death domain (FADD) is crucial for extrinsic apoptosis.
  • The role of FADD in intrinsic necrosis remains largely unexplored.

Purpose of the Study:

  • To investigate the role of FADD SUMOylation in intrinsic necrosis.
  • To elucidate the molecular mechanisms linking FADD to necrosis.

Main Methods:

  • SUMOylation assays
  • Co-immunoprecipitation
  • In vitro and in vivo cell models of necrosis
  • Analysis of protein-protein interactions
  • Mitochondrial fragmentation assessment

Main Results:

  • FADD undergoes SUMOylation at multiple lysine residues (K120/125/149) by SUMO2 during necrosis induced by calcium ionophore A23187 and ischemic damage.
  • SUMOylated FADD interacts with dynamin-related protein 1 (Drp1), promoting its recruitment to mitochondria and subsequent fragmentation.
  • Mitochondrial fragmentation-dependent necrosis is inhibited by FADD or Drp1 deficiency or expression of SUMO-defective FADD.
  • Caspase-10, but not caspase-8, forms a complex with SUMO-FADD/Drp1 on mitochondria, enhancing Drp1 oligomerization and necrosis.
  • Specific caspase-10 mutants associated with autoimmune lymphoproliferative syndrome and non-Hodgkin lymphoma modulate this necrotic pathway.

Conclusions:

  • FADD SUMOylation is an essential step in intrinsic necrosis.
  • SUMOylated FADD acts as a scaffold for Drp1 and caspase-10, driving mitochondrial fragmentation and cell death.
  • This pathway offers novel insights into regulated necrosis mechanisms triggered by calcium overload and ischemia.
Keywords:
DRP1FADDSUMOylationcaspase-10necrosis

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