title: Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis.
abstract: Autophagy and apoptosis are two evolutionarily conserved processes that regulate cell fate in response to cytotoxic stress. However, the functional relationship between these two processes remains far from clear. Here, we demonstrate an autophagy-dependent mechanism of caspase-8 activation and initiation of the apoptotic cascade in response to SKI-I, a pan-sphingosine kinase inhibitor, and bortezomib, a proteasome inhibitor. Autophagy is induced concomitantly with caspase-8 activation, which is responsible for initiation of the caspase cascade and the mitochondrial amplification loop that is required for full execution of apoptosis. Inhibition of autophagosome formation by depletion of Atg5 or Atg3 results in a marked suppression of caspase-8 activation and apoptosis. Although caspase-8 self-association depends on p62/SQSTM1, its self-processing requires the autophagosomal membrane. Caspase-8 forms a complex with Atg5 and colocalizes with LC3 and p62. Moreover, FADD, an adaptor protein for caspase-8 activation, associates with Atg5 on Atg16L- and LC3-positive autophagosomal membranes and loss of FADD suppresses cell death. Taken together, these results indicate that the autophagosomal membrane serves as a platform for an intracellular death-inducing signaling complex (iDISC) that recruits self-associated caspase-8 to initiate the caspase-8/-3 cascade.
authors.affiliation: Department of Pharmacology and Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Young
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Osman
authors.initials: O
authors.lastname: Khan
authors.forename: Sungman
authors.initials: S
authors.lastname: Park
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Hori
authors.forename: Jong
authors.initials: J
authors.lastname: Yun
authors.forename: Arun K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Chang-Deng
authors.initials: CD
authors.lastname: Hu
authors.forename: Jianke
authors.initials: J
authors.lastname: Zhang
authors.forename: Mark
authors.initials: M
authors.lastname: Kester
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000502:physiology*; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D055786:Gene Knockout Techniques; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport; D011720:Pyrazoles / Q000494:pharmacology; D000071456:Sequestosome-1 Protein; D014407:Tumor Cells, Cultured; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D000099157:Sphingosine Kinase; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D053148:Caspase 3; D053181:Caspase 8; D053418:Death Domain Receptor Signaling Adaptor Proteins; D053200:Fas-Associated Death Domain Protein; D006360:Heat-Shock Proteins; D006834:Hydrazines; D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D011720:Pyrazoles; D000071456:Sequestosome-1 Protein; D044763:Ubiquitin-Conjugating Enzymes; D000099157:Sphingosine Kinase; C495773:Atg5 protein, mouse; C505534:Fadd protein, mouse; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C556356:N'-((2-hydroxy-1-naphthyl)methylene)-3-(2-naphthyl)-1H-pyrazole-5-carbohydrazide; C101343:Sqstm1 protein, mouse; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C568853:Atg3 protein, mouse