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J. Biol. Chem., Vol. 283, Issue 18, 11905-11912, May 2, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/18/11905    most recent M710557200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Luo, D. Articles by Min, W. PubMed PubMed Citation Articles by Luo, D. Articles by Min, W. Social Bookmarking                      What's this?

AIP1 Is Critical in Transducing IRE1-mediated Endoplasmic Reticulum Stress Response^*

Dianhong Luo, Yun He, Haifeng Zhang, Luyang Yu, Hong Chen, Zhe Xu, Shibo Tang¹, Fumihiko Urano^¶, and Wang Min²

From the Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China, and ^¶Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts 01605

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-PH), 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.

Received for publication, December 28, 2007 , and in revised form, February 11, 2008.

^* This work was supported by National Institutes of Health Grants R01 HL65978-5, R01 HL077357-1, and P01 HL070295-6, an Established Investigator Award from the American Heart Association (0440172N) (to W. M.), and National Natural Science Foundation of China Grant 30772392 (to S. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed. E-mail: tangsb{at}mail.sysu.edu.cn. ² To whom correspondence may be addressed: Interdepartmental Program in Vascular Biology and Transplantation and Dept. of Pathology, Yale University School of Medicine, 10 Amistad St., New Haven, CT 06520. Tel.: 203-785-6047; Fax: 203-737-2293; E-mail: wang.min{at}yale.edu.

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