Figure 1. ER stress-induced apoptosis.
The accumulation of malfolded proteins in the ER triggers the activation of PERK,
Irel, and ATF6, which mount the unfolded protein response. PERK and Irel
undergo autophosphorylation (P), resulting in the activation of their kinase
domains. PERK shuts down translation by phosphorylating eIF2α, while the
endonuclease domain of Irel cleaves XBP-1 mRNA, generating a new XBP-1
protein competent in activating the promoters of chaperone genes. Cleavage of the
cytosolic tail of ATF6 at the ER frees the transcription factor domain, which enters
the nucleus and activates transcription of XBP-1 and chaperone genes. Irel signaling
also induces the recruitment and activation of JNK via TRAF2. Activated JNK and
c-Abl may translocate to the mitochondria and phosphorylate unidentified
regulators of Cyt.c release. Release of Ca2+ from the ER increases the [Ca2+]c,
causing calcineurin-dependent dephosphorylation of BAD, which is released from
14–3-3 and translocates to mitochondria, inducing the homooligomerization of
BAX and BAK. BAX/BAK pores in the OMM may induce the release of Cyt.c and
other apoptotic IMS proteins into the cytosol, resulting in the activation of effector
caspases. CHOP may assist this process by downregulation expression of the Bcl-2,
which prevents the activation of BAX/BAK and Cyt.c release. Calpain is also
activated by increased [Ca2+]c and cleaves caspase-12 at the ER membrane,
releasing a p20/p10 fragment into the cytosol, which may undergo self-processing,
generating the p20/p10 heterotetrameric active enzyme. Active caspase-12 may
cleave and activate downstream effector caspases or other unidentified substrates.106 GENETICS OF APOPTOSIS