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*

By T. Yoneda, K. Imaizumi, Kayoko Oono, Daishi Yui, F. Gomi, T. Katayama, M. Tohyama. Journal of Biological Chemistry, 2001

879 citations recorded by the source corpus.

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 IRE1α, and JIK was seen to modulate IRE1α-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.

Subfields: Cell Biology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7f7f282a3e0baa9ddb0d6184f7c9af3c7dbc794f

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In Cell Biology

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In Epidemiology

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In Molecular Biology

1. R. Kaufman
2. J. Malhotra
3. Jerry M. Adams
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5. A. Gorman
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7. Jun Wu
8. P. Pinton

Citations in the corpus

• From acute ER stress to physiological roles of the Unfolded Protein Response (2006, background): “pase-12 from TRAF2, which is required for the activation of procaspase-12.(47)”
• Orchestrating the unfolded protein response in health and disease. (2002, background): “As shown in Figure 2, release of TRAF2 permits clustering of procaspase-12 at the ER membrane, leading to its activation (40).”
• Ways of dying: multiple pathways to apoptosis. (2003, background): “TRAF2, a factor that associates with death receptors, has also been reported to interact with procaspase-12 and promote its self-processing (Yoneda et al. 2001).”
• Endoplasmic Reticulum Stress in Liver Disease (2010, background): “In mice, caspase 12 activation can occur via IRE1a-TRAF2 induced recruitment and activation of procaspase 12 [153].”