Fig. 3

Role of GRP78 in cellular apoptosis. In the case of strong and persistent ER stress, GRP78 is upregulated, which promotes the production and release of Ca²⁺. GRP78 activates UPR signaling to upregulate CHOP and induce cellular apoptosis. Increased [Ca²⁺] induces apoptosis in a mitochondrial-dependent pathway by increasing Bax and decreasing Bcl-2 expression. In addition, Ca²⁺ released into the cytoplasm can also activate calpain. Activated calpain promotes the cleavage of caspase-12 and mediates apoptosis through a cascade reaction. JNK is also activated by dimerized IRE1 via TRAF2-ASK1 signaling to induce apoptosis. Persistent ER stress can cause excess ROS production, and high ROS levels can induce ER stress, forming a vicious cycle. GRP78 can reduce the release of mitochondrial cytochrome c to inhibit apoptosis by stabilizing the expression and activity of Raf-1