Transcription factor XBP1s, activated by endoplasmic reticulum (ER) stress in a dose-dependent manner, plays a central role in adaptive unfolded protein response (UPR) via direct activation of multiple genes controlling protein refolding. Here, we report that elevation of ER stress above a critical threshold causes accumulation of XBP1s protein sufficient for binding to the promoter and activation of a gene encoding a transcription factor KLF9. In comparison to other XBP1s targets, KLF9 promoter contains an evolutionary conserved lower-affinity binding site that requires higher amounts of XBP1s for activation. In turn, KLF9 induces expression of two regulators of ER calcium storage, TMEM38B and ITPR1, facilitating additional calcium release from ER, exacerbation of ER stress, and cell death. Accordingly, Klf9 deficiency attenuates tunicamycin-induced ER stress in mouse liver. These data reveal a role for XBP1s in cytotoxic UPR and provide insights into mechanisms of life-or-death decisions in cells under ER stress.
Pubmed ID: 30282030 RIS Download
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View all literature mentionsThis unknown targets TMEM38B
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View all literature mentionsThis unknown targets mouse-IgG-control
View all literature mentionsThis monoclonal targets alpha Tubulin (TU-02)
View all literature mentionsThis monoclonal targets Mouse XBP-1
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View all literature mentionsThis polyclonal targets goat anti-rabbit IgG-HRP
View all literature mentionsThis polyclonal targets donkey anti-goat IgG-HRP
View all literature mentionsThis unknown targets IP3 Receptor 1
View all literature mentionsThis unknown targets TMEM38B
View all literature mentionsThis polyclonal targets Mouse IgG
View all literature mentionsThis monoclonal targets Mouse XBP-1
View all literature mentionsThis monoclonal targets alpha Tubulin (TU-02)
View all literature mentionsThis unknown targets IP3 Receptor 1
View all literature mentionsThis polyclonal targets goat anti-rabbit IgG-HRP
View all literature mentionsThis polyclonal targets donkey anti-goat IgG-HRP
View all literature mentionsThis unknown targets TMEM38B
View all literature mentionsThis unknown targets mouse-IgG-control
View all literature mentions