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Fine Tuning of the UPR by the Ubiquitin Ligases Siah1/2.
- Source :
-
PLoS Genetics . May2014, Vol. 10 Issue 5, p1-26. 26p. - Publication Year :
- 2014
-
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]
Details
- Language :
- English
- ISSN :
- 15537390
- Volume :
- 10
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- PLoS Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 96281758
- Full Text :
- https://doi.org/10.1371/journal.pgen.1004348