AIP1 is critical in transducing IRE1-mediated endoplasmic reticulum stress response
Program in Gene Function and Expression; Program in Molecular Medicine
Medical Subject Headings
Animals; Apoptosis; Cattle; DNA-Binding Proteins; Dimerization; Endoplasmic Reticulum; Endothelial Cells; Enzyme Activation; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinase 5; Membrane Proteins; Mice; Mice, Knockout; Protein Binding; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases; *Signal Transduction; Transcription Factors; ras GTPase-Activating Proteins
Genetics and Genomics
We 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.
Rights and Permissions
Citation: J Biol Chem. 2008 May 2;283(18):11905-12. Epub 2008 Feb 15. Link to article on publisher's site