Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8.
The involvement of the death adaptor protein FADD and the apoptosis-initiating caspase-8 in CD95 and TRAIL death signalling has recently been demonstrated by the analysis of the native death-inducing signalling complex (DISC) that forms upon ligand-induced receptor cross-linking. However, the role of caspase-10, the other death-effector-domain-containing caspase besides caspase-8, in death receptor signalling has been controversial. Here we show that caspase-10 is recruited not only to the native TRAIL DISC but also to the native CD95 DISC, and that FADD is necessary for its recruitment to and activation at these two protein complexes. With respect to the function of caspase-10, we show that it is not required for apoptosis induction. In addition, caspase-10 can not substitute for caspase-8, as the defect in apoptosis induction observed in caspase-8-deficient cells could not be rescued by overexpression of caspase-10. Finally, we demonstrate that caspase-10 is cleaved during CD95-induced apoptosis of activated T cells. These results show that caspase-10 activation occurs in primary cells, but that its function differs from that of caspase-8.
Sprick
Martin R
MR
Division for Apoptosis Regulation, Tumour Immunology Program, DKFZ, Heidelberg, Germany.
Rieser
Eva
E
Stahl
Heiko
H
Grosse-Wilde
Anne
A
Weigand
Markus A
MA
Walczak
Henning
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001402:B-Lymphocytes / Q000378:metabolism; D016466:CHO Cells; D002352:Carrier Proteins / Q000502:physiology*; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D004790:Enzyme Induction; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D019169:Jurkat Cells / Q000378:metabolism; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; C506438:CASP10 protein, human