title: SUMO-Modified FADD Recruits Cytosolic Drp1 and Caspase-10 to Mitochondria for Regulated Necrosis.
abstract: 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.
authors: Department of Biological Science, Seoul National University, Seoul, South Korea.
authors: Seon-Guk
authors: SG
authors: Choi
authors: Department of Biological Science, Seoul National University, Seoul, South Korea.
authors: Hyunjoo
authors: H
authors: Kim
authors: Department of Biological Science, Seoul National University, Seoul, South Korea.
authors: Eun Il
authors: EI
authors: Jeong
authors: Department of Biological Science, Seoul National University, Seoul, South Korea.
authors: Ho-June
authors: HJ
authors: Lee
authors: Department of Biological Science, Seoul National University, Seoul, South Korea.
authors: Sungwoo
authors: S
authors: Park
authors: Department of Biological Science, Seoul National University, Seoul, South Korea.
authors: Song-Yi
authors: SY
authors: Lee
authors: Department of Biological Science, Seoul National University, Seoul, South Korea.
authors: Hyeon-Jeong
authors: HJ
authors: Lee
authors: Department of Biological Science, Seoul National University, Seoul, South Korea.
authors: Seong Won
authors: SW
authors: Lee
authors: Department of Biological Science, Seoul National University, Seoul, South Korea.
authors: Chin Ha
authors: CH
authors: Chung
authors: Department of Biological Science, Seoul National University, Seoul, South Korea ykjung@snu.ac.kr.
authors: Yong-Keun
authors: YK
authors: Jung
mesh_terms: D000818:Animals; D053455:Caspase 10 / Q000378:metabolism*; D015687:Cell Hypoxia; D003600:Cytosol / Q000378:metabolism*; D034281:Dynamins / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009336:Necrosis; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D058207:Sumoylation
chemical_list: C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D046912:Multiprotein Complexes; D050505:Mutant Proteins; D034741:RNA, Small Interfering; D025842:SUMO-1 Protein; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D053455:Caspase 10; D034281:Dynamins; D008239:Lysine
keywords: DRP1; FADD; SUMOylation; caspase-10; necrosis