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 ca...

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Bibliographic Details
Published in:Molecular and cellular biology 2017-01, Vol.37 (2)
Main Authors: Choi, Seon-Guk, Kim, Hyunjoo, Jeong, Eun Il, Lee, Ho-June, Park, Sungwoo, Lee, Song-Yi, Lee, Hyeon-Jeong, Lee, Seong Won, Chung, Chin Ha, Jung, Yong-Keun
Format: Article
Language:English
Subjects:
Animals
Caspase 10 - metabolism
caspase-10
Cell Hypoxia
Cytosol - metabolism
DRP1
Dynamins - metabolism
FADD
Fas-Associated Death Domain Protein - metabolism
HEK293 Cells
HeLa Cells
Humans
Lysine - metabolism
Mice, Inbred C57BL
Mitochondria - metabolism
Multiprotein Complexes - metabolism
Mutant Proteins - metabolism
Necrosis
Protein Binding
Protein Multimerization
Protein Transport
RNA, Small Interfering - metabolism
Small Ubiquitin-Related Modifier Proteins - metabolism
SUMO-1 Protein - metabolism
SUMOylation
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Summary: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.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.00254-16