1. Fine Tuning of the UPR by the Ubiquitin Ligases Siah1/2.
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Scortegagna, Marzia, Kim, Hyungsoo, Li, Jian-Liang, Yao, Hang, Brill, Laurence M., Han, Jaeseok, Lau, Eric, Bowtell, David, Haddad, Gabriel, Kaufman, Randal J., and Ronai, Ze'ev A.
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UBIQUITIN ligases ,ENDOPLASMIC reticulum ,ISCHEMIA ,PROLINE hydroxylase ,HYDROXYLATION - Abstract
The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell death. We show that high levels of ER stress (i.e., ischemia-like conditions) induce transcription of the ubiquitin ligases Siah1/2 through the UPR transducers PERK/ATF4 and IRE1/sXBP1. In turn, Siah1/2 attenuates proline hydroxylation of ATF4, resulting in its stabilization, thereby augmenting ER stress output. Conversely, ATF4 activation is reduced upon Siah1/2 KD in cultured cells, which attenuates ER stress-induced cell death. Notably, Siah1a
+/− ::Siah2−/− mice subjected to neuronal ischemia exhibited smaller infarct volume and were protected from ischemia-induced death, compared with the wild type (WT) mice. In all, Siah1/2 constitutes an obligatory fine-tuning mechanism that predisposes cells to death under severe ER stress conditions. [ABSTRACT FROM AUTHOR]- Published
- 2014
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