title: DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD.
abstract: DJ-1 was initially identified as an oncogene product involved in human tumorigenesis in cooperation with Ras. Increased DJ-1 expression is associated with tumorigenesis in many cancers, whereas the loss of DJ-1 function is linked to an autosomal recessive form of Parkinson's disease (PD). It has been reported that DJ-1 protects cells from TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis. However, the mechanism by which DJ-1 is involved is still largely unknown. Here we show that DJ-1 inhibits TRAIL-induced apoptosis by blocking Fas-associated protein death domain (FADD)-mediated pro-caspase-8 activation. Wild-type DJ-1, but not the PD-associated mutant L166P, binds to FADD to inhibit the formation of the death-inducing signaling complex (DISC). DJ-1 competes with pro-caspase-8 to bind to FADD at the death effector domain, thereby repressing the recruitment and activation of pro-caspase-8 to the active form of caspase-8. Thus, our study suggests that DJ-1 protects against TRAIL-induced apoptosis through the regulation of DISC formation.
authors.affiliation: Laboratory of Molecular Neuropathology, Department of Neurobiology, Key Laboratory of Brain Function and Disease and School of Life Sciences, University of Science & Technology of China, Chinese Academy of Sciences, Hefei, Anhui, PR China.
authors.forename: K
authors.initials: K
authors.lastname: Fu
authors.forename: H
authors.initials: H
authors.lastname: Ren
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: E
authors.initials: E
authors.lastname: Fei
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: G
authors.initials: G
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism*; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D015513:Oncogene Proteins / Q000502:physiology*; D000071617:Protein Deglycase DJ-1; D021381:Protein Transport; D012333:RNA, Messenger / Q000032:analysis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D061945:Caspase Inhibitors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D016159:Tumor Suppressor Protein p53; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D053181:Caspase 8