Luo, DianhongHe, YunZhang, HaifengYu, LuyangChen, HongXu, ZheTang, ShiboUrano, FumihikoMin, Wang2022-08-232022-08-232008-02-192011-04-19J Biol Chem. 2008 May 2;283(18):11905-12. Epub 2008 Feb 15. <a href="http://dx.doi.org/10.1074/jbc.M710557200">Link to article on publisher's site</a>0021-9258 (Linking)10.1074/jbc.M71055720018281285https://hdl.handle.net/20.500.14038/44119We have previously shown that ASK1-interacting protein 1 (AIP1) transduces tumor necrosis factor-induced ASK1-JNK signaling. Because endoplasmic reticulum (ER) stress activates ASK1-JNK signaling cascade, we investigated the role of AIP1 in ER stress-induced signaling. We created AIP1-deficient mice (AIP1-KO) from which mouse embryonic fibroblasts and vascular endothelial cells were isolated. AIP1-KO cells show dramatic reductions in ER stress-induced, but not oxidative stress-induced, ASK1-JNK activation and cell apoptosis. The ER stress-induced IRE1-JNK/XBP-1 axis, but not the PERK-CHOP1 axis, is blunted in AIP1-KO cells. ER stress induced formation of an AIP1-IRE1 complex, and the PH domain of AIP1 is critical for the IRE1 interaction. Furthermore, reconstitution of AIP1-KO cells with AIP1 wild type, not an AIP1 mutant with a deletion of the PH domain (AIP1-DeltaPH), restores ER stress-induced IRE1-JNK/XBP-1 signaling. AIP1-IRE1 association facilitates IRE1 dimerization, a critical step for activation of IRE1 signaling. More importantly, AIP1-KO mice show impaired ER stress-induced IRE1-dependent signaling in vivo. We conclude that AIP1 is essential for transducing the IRE1-mediated ER stress response.en-USAnimalsApoptosisCattleDNA-Binding ProteinsDimerizationEndoplasmic ReticulumEndothelial CellsEnzyme ActivationHumansJNK Mitogen-Activated Protein KinasesMAP Kinase Kinase Kinase 5Membrane ProteinsMiceMice, KnockoutProtein BindingProtein Structure, TertiaryProtein-Serine-Threonine Kinases*Signal TransductionTranscription Factorsras GTPase-Activating ProteinsGenetics and GenomicsJournal Articlehttps://escholarship.umassmed.edu/pgfe_pp/921946747pgfe_pp/92