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 starvati on, and perturbation of calcium homeostasis, cells respond to the stress by increasing transcription of genes encoding ER molecular chaperones, a proc ess known as unfolded protein response. The signaling is initiated by IRE1s , ER stress sensors. Alternatively, excessive stress to the ER results in a poptosis, Caspase la is known to be essential for this ER stress-induced ap optosis. In this study, we analyzed the detailed regulatory mechanisms of I RE1s during ER stress. We identified c-Jun N-terminal inhibitory kinase (JI K) as a binding partner of IRE1 alpha, and JIK was seen to modulate IRE1 al pha -TRAF2 (tumor necrosis factor receptor associated factor 2) complex for mation and the resultant alteration to c-Jun N-terminal kinase signaling fr om IRE1s in response to ER stress. We also demonstrated that TRAF2 interact s with procaspase-12 and promotes the clustering of procaspase-12 and its a ctivation 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-termina l 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 apopto sis-signaling pathway, one which connects the stress sensor molecule IRE1 a nd the activation of caspase-12.