| First Author | Scortegagna M | Year | 2014 |
| Journal | PLoS Genet | Volume | 10 |
| Issue | 5 | Pages | e1004348 |
| PubMed ID | 24809345 | Mgi Jnum | J:232292 |
| Mgi Id | MGI:5776449 | Doi | 10.1371/journal.pgen.1004348 |
| Citation | Scortegagna M, et al. (2014) Fine tuning of the UPR by the ubiquitin ligases Siah1/2. PLoS Genet 10(5):e1004348 |
| abstractText | 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. |
