Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress.
When accumulation of a malfolded protein in the endoplastic reticulum (ER) is induced by various adverse conditions, such as hypoxia, glucose starvation, and perturbation of calcium homeostasis, cells respond to the stress by increasing transcription of genes encoding ER molecular chaperones, a process known as unfolded protein response. The signaling is initiated by IRE1s, ER stress sensors. Alternatively, excessive stress to the ER results in apoptosis. Caspase-12 is known to be essential for this ER stress-induced apoptosis. In this study, we analyzed the detailed regulatory mechanisms of IRE1s during ER stress. We identified c-Jun N-terminal inhibitory kinase (JIK) as a binding partner of IRE1alpha, and JIK was seen to modulate IRE1alpha-TRAF2 (tumor necrosis factor receptor-associated factor 2) complex formation and the resultant alteration to c-Jun N-terminal kinase signaling from IRE1s in response to ER stress. We also demonstrated that TRAF2 interacts with procaspase-12 and promotes the clustering of procaspase-12 and its activation by cleavage in response to ER stress. These results indicate that TRAF2 plays crucial roles not only in the signaling of the c-Jun N-terminal kinase pathway but also in activation of caspase-12 to transduce signals from IRE1s. Thus, we provide a missing link in the ER stress-induced apoptosis-signaling pathway, one which connects the stress sensor molecule IRE1 and the activation of caspase-12.
Department of Anatomy and Neuroscience, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. yoneda@anat2.med.osaka-u.ac.jp
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Yoneda
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Imaizumi
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Oono
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Yui
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Gomi
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Katayama
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Tohyama
D017209:Apoptosis; D053454:Caspase 12; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D011498:Protein Precursors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D047992:TNF Receptor-Associated Factor 2; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology; D020798:Two-Hybrid System Techniques
D011498:Protein Precursors; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D014415:Tunicamycin; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C506444:CASP12 protein, human; D053454:Caspase 12; D020169:Caspases