Endoplasmic reticulum stress: cell life and death decisions

Abstract

Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response, which is aimed initially at compensating for damage but can eventually trigger cell death if ER dysfunction is severe or prolonged. The mechanisms by which ER stress leads to cell death remain enigmatic, with multiple potential participants described but little clarity about which specific death effectors dominate in particular cellular contexts. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes.

Figure 1

Signal transduction events associated with ER stress. Chaperone Grp78 binds the N-termini of Ire1, PERK, and ATF6, preventing their activation. Unfolded proteins in the ER cause Grp78 to release Ire1, PERK, and ATF6. Upon Grp78 release, Ire1 and PERK oligomerize in ER membranes. Oligomerized Ire1 binds TRAF2, signaling downstream kinases that activate NF-κB and c-Jun (AP-1), causing expression of genes associated with host defense (alarm). The intrinsic ribonuclease activity of Ire1 also results in production of XBP-1, a transcription factor that induces expression of genes involved in restoring protein folding or degrading unfolded proteins. Oligomerization of PERK activates its intrinsic kinase activity, resulting in phosphorylation of eIF2α and suppression of mRNA translation. Under these conditions, only selected mRNAs, including ATF4, are translated. ATF4 induces expression of genes involved in restoring ER homeostasis. Release of Grp78 from ATF6 allows this protein to translocate to the Golgi apparatus for proteolytic processing to release active ATF6, which controls expression of UPR genes.

Figure 2

Cell death mechanisms induced by ER stress. Several of the proposed pathways linking ER stress to cell death are depicted. Dashed lines indicate protein translocation events (c-Abl, Jafrac2). The mitochondrial permeability transition pore complex, which is Ca²⁺-sensitive, is not shown in the diagram. See the text for additional details.