Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis

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Science  04 Jul 2014:
Vol. 345, Issue 6192, pp. 98-101
DOI: 10.1126/science.1254312

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Life and death and quality control

When cells are subjected to too much stress, they curl up their toes and die. Lu et al. describe a clever strategy cells use to stay alive as long as they are not stressed for too long. The cells' quality-control machinery will activate a so-called death receptor when defective proteins accumulate within the cell, a sign of stress—but they will wait until the proteins have built up for a good long time. If stress is relieved soon enough, levels of the death receptor decay back to normal, and the cells stay alive; otherwise, R.I.P.

Science, this issue p. 98


Protein folding by the endoplasmic reticulum (ER) is physiologically critical; its disruption causes ER stress and augments disease. ER stress activates the unfolded protein response (UPR) to restore homeostasis. If stress persists, the UPR induces apoptotic cell death, but the mechanisms remain elusive. Here, we report that unmitigated ER stress promoted apoptosis through cell-autonomous, UPR-controlled activation of death receptor 5 (DR5). ER stressors induced DR5 transcription via the UPR mediator CHOP; however, the UPR sensor IRE1α transiently catalyzed DR5 mRNA decay, which allowed time for adaptation. Persistent ER stress built up intracellular DR5 protein, driving ligand-independent DR5 activation and apoptosis engagement via caspase-8. Thus, DR5 integrates opposing UPR signals to couple ER stress and apoptotic cell fate.

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