title: TNF-alpha induces two distinct caspase-8 activation pathways.
abstract: The inflammatory response of mammalian cells to TNF-alpha can be switched to apoptosis either by cotreatment with a protein synthesis inhibitor, cycloheximide, or Smac mimetic, a small molecule mimic of Smac/Diablo protein. Cycloheximide promotes caspase-8 activation by eliminating endogenous caspase-8 inhibitor, c-FLIP, while Smac mimetic does so by triggering autodegradation of cIAP1 and cIAP2 (cIAP1/2), leading to the release of receptor interacting protein kinase (RIPK1) from the activated TNF receptor complex to form a caspase-8-activating complex consisting of RIPK1, FADD, and caspase-8. This process also requires the action of CYLD, a RIPK1 K63 deubiquitinating enzyme. RIPK1 is critical for caspase-8 activation-induced by Smac mimetic but dispensable for that triggered by cycloheximide. Moreover, Smac mimetic-induced caspase-8 activation is not blocked by endogenous c-FLIP. These findings revealed that TNF-alpha is able to induce apoptosis via two distinct caspase-8 activation pathways that are differentially regulated by cIAP1/2 and c-FLIP.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Lai
authors.initials: L
authors.lastname: Wang
authors.forename: Fenghe
authors.initials: F
authors.lastname: Du
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D018716:Molecular Mimicry; D046912:Multiprotein Complexes / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D011500:Protein Synthesis Inhibitors; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C505530:CASP8 protein, human; D053181:Caspase 8