cell stress model (IMAGE)
Caption
Proposed model illustrating chaperone-mediated and BAX/BAK-dependent pathways of ER protein redistribution. (A) Under unstressed conditions, DNAJB12 and DNAJB14 primarily function in their canonical ER-associated degradation (ERAD) pathway, promoting the proteasomal degradation of ER membrane proteins, including BIK. (B) During mild, non-apoptotic ER stress, DNAJB12 and DNAJB14 form a complex with cytosolic chaperones to mediate the reflux of proteins from the ER lumen to the cytosol through a DNAJB12/14-dependent, redox-regulated, chaperone-mediated pathway (ERCYS). At the same time, DNAJB12 facilitates the proteasomal degradation of BIK, preventing the recruitment of BAX and BAK to the ER membrane. (C) During severe ER stress or under highly reducing conditions, elevated glutathione levels reduce the intramolecular disulfide bonds of DNAJB12 and DNAJB14, triggering their proteasomal degradation. Loss of DNAJB12/14 abolishes ERCYS and stabilizes BIK, which promotes the recruitment and oligomerization of BAX and BAK at the ER membrane. This results in ER membrane permeabilization and the initiation of apoptotic cell death.
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Dr. Aeid Ifbaria
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