biostudies-literatureScortegagna MNIDDK NIH HHSNHLBI NIH HHSNCI NIH HHSPHS HHSe1004348https://www.ebi.ac.uk/biostudies/studies/S-EPMC4014425biostudies-literatureUnknown10(5)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 ischPLoS geneticsFine tuning of the UPR by the ubiquitin ligases Siah1/2.PMC4014425R01 CA099961NIH/NHLBI R01 HL052173NIH/NCI R01 CA128814P01 HL098053P01 CA128814NIH/NHLBI P01 HL098053P30 CA030199R01 HL052173NIH/NCI R01 CA099961NIH/NIDDK R37 DK042394R37 DK042394R01 DK088227NIH/NIDDK R01DK088227Scortegagna MKim HKaufman RJHaddad GLau ELi JLHan JYao HBrill LMRonai ZABowtell DfalseFine tuning of the UPR by the ubiquitin ligases Siah1/2.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 isch2014-01-01T00:00:00Z2014 May2025-04-22T02:49:10.048Z2019-06-06T12:43:13ZS-EPMC40144252480934510.1371/journal.pgen.1004348