title: Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death.
abstract: Autophagic cell death is characterized by the accumulation of vacuoles in physiological and pathological conditions. However, its molecular event is unknown. Here, we show that Atg5, which is known to function in autophagy, contributes to autophagic cell death by interacting with Fas-associated protein with death domain (FADD). Down-regulation of Atg5 expression in HeLa cells suppresses cell death and vacuole formation induced by IFN-gamma. Inversely, ectopic expression of Atg5 using adenoviral delivery induces autophagic cell death. Deletion mapping analysis indicates that procell death activity resides in the middle and C-terminal region of Atg5. Cells harboring the accumulated vacuoles triggered by IFN-gamma or Atg5 expression become dead, and vacuole formation precedes cell death. 3-Methyladenine or expression of Atg5(K130R) mutant blocks both cell death and vacuole formation triggered by IFN-gamma, whereas benzyloxycarbonyl-VAD-fluoromethyl ketone (Z-VAD-fmk) inhibits only cell death but not vacuole formation. Atg5 interacts with FADD via death domain in vitro and in vivo, and the Atg5-mediated cell death, but not vacuole formation, is blocked in FADD-deficient cells. These results suggest that Atg5 plays a crucial role in IFN-gamma-induced autophagic cell death by interacting with FADD.
authors.affiliation: Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
authors.forename: Jong-Ok
authors.initials: JO
authors.lastname: Pyo
authors.forename: Mi-Hee
authors.initials: MH
authors.lastname: Jang
authors.forename: Yun-Kyung
authors.initials: YK
authors.lastname: Kwon
authors.forename: Ho-June
authors.initials: HJ
authors.lastname: Lee
authors.forename: Joon-Il
authors.initials: JI
authors.lastname: Jun
authors.forename: Ha-Na
authors.initials: HN
authors.lastname: Woo
authors.forename: Dong-Hyung
authors.initials: DH
authors.lastname: Cho
authors.forename: Boyoun
authors.initials: B
authors.lastname: Choi
authors.forename: Heuiran
authors.initials: H
authors.lastname: Lee
authors.forename: Joo-Hang
authors.initials: JH
authors.lastname: Kim
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Oshumi
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000502:physiology*; D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D001665:Binding Sites; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D053200:Fas-Associated Death Domain Protein; D017353:Gene Deletion; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016296:Mutagenesis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012441:Saccharomyces cerevisiae; D014162:Transfection; D020798:Two-Hybrid System Techniques; D014617:Vacuoles / Q000187:drug effects / Q000502:physiology*
chemical_list: C502778:ATG5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000590:Amino Acid Chloromethyl Ketones; D000071187:Autophagy-Related Protein 5; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D008869:Microtubule-Associated Proteins; D016376:Oligonucleotides, Antisense; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C025946:3-methyladenine; D007371:Interferon-gamma; D000225:Adenine