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


Fas-associated protein with death domain (FADD) plays a key role in extrinsic apoptosis. Here, we show that FADD is SUMOylated as an essential step during intrinsic necrosis. FADD was modified at multiple lysine residues (K120/125/149) by small ubiquitin-related modifier 2 (SUMO2) during necrosis caused by calcium ionophore A23187 and by ischemic damage. SUMOylated FADD bound to dynamin-related protein 1 (Drp1) in cells both in vitro and in ischemic tissue damage cores, thus promoting Drp1 recruitment by mitochondrial fission factor (Mff) to accomplish mitochondrial fragmentation. Mitochondrial-fragmentation-associated necrosis was blocked by FADD or Drp1 deficiency and SUMO-defective FADD expression. Interestingly, caspase-10, but not caspase-8, formed a ternary protein complex with SUMO-FADD/Drp1 on the mitochondria upon exposure to A23187 and potentiated Drp1 oligomerization for necrosis. Moreover, the caspase-10 L285F and A414V mutants, found in autoimmune lymphoproliferative syndrome and non-Hodgkin lymphoma, respectively, regulated this necrosis. Our study reveals an essential role of SUMOylated FADD in Drp1- and caspase-10-dependent necrosis, providing insights into the mechanism of regulated necrosis by calcium overload and ischemic injury.

DOI: 10.1128/MCB.00254-16

Cite this paper

@article{Choi2017SUMOModifiedFR, title={SUMO-Modified FADD Recruits Cytosolic Drp1 and Caspase-10 to Mitochondria for Regulated Necrosis.}, author={Seon-Guk Choi and Hyunjoo Kim and Eun Il Jeong and Ho-June Lee and Sungwoo Park and S Lee and Hyeon Jeong Lee and Seong Won Lee and Chin Ha Chung and Yong-Keun Jung}, journal={Molecular and cellular biology}, year={2017}, volume={37 2} }