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J. Biol. Chem., Vol. 280, Issue 15, 15061-15070, April 15, 2005

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Tumor Necrosis Factor -induced Desumoylation and Cytoplasmic Translocation of Homeodomain-interacting Protein Kinase 1 Are Critical for Apoptosis Signal-regulating Kinase 1-JNK/p38 Activation^*

Xianghong Li, Rong Zhang, Dianhong Luo, Sang-Joon Park¶, Qian Wang, Yongsok Kim¶, and Wang Min||

From the Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, the ^¶Laboratory Research Program, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, and the Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China

The apoptosis signal-regulating kinase 1 (ASK1)-JNK/p38 signaling pathway is pivotal component in cell apoptosis and can be activated by a variety of death stimuli including tumor necrosis factor (TNF) and oxidative stress (reactive oxygen species). However, the mechanism for ASK1 activation is not fully understood. We have recently identified ASK1-interacting protein (AIP1) as novel signal transducer in TNF-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3. In the present study, we employed yeast two-hybrid system using the N-terminal domain of AIP1 as bait and identified homeodomain-interacting protein kinase 1 (HIPK1) as an AIP1-associated protein. Interestingly, we showed that TNF induced HIPK1 desumoylation concomitant with a translocation from nucleus to cytoplasm at 15 min followed by a return to nucleus by 60 min. The kinetics of HIPK1 translocation correlates with those of stress-induced ASK1-JNK/P38 activation. A specific JNK inhibitor blocked the reverse but not the initial translocation of HIPK1, suggesting that the initial translocation is an upstream event of ASK1-JNK/p38 signaling and JNK activation regulates the reverse translocation as a feedback mechanism. Consistently, expression of HIPK1 increased, whereas expression of a kinase-inactive form (HIPK1-D315N) or small interference RNA of HIPK1 decreased stress-induced ASK1-JNK/P38 activation without effects on IKK-NF-B signaling. Moreover, a sumoylation-defective mutant of HIPK1 (KR5) localizes to the cytoplasm and is constitutively active in ASK1-JNK/P38 activation. Furthermore, HIPK1-KR5 induces dissociation of ASK1 from its inhibitors 14-3-3 and thioredoxin and synergizes with AIP1 to induce ASK1 activation. Our study suggests that TNF-induced desumoylation and cytoplasmic translocation of HIPK1 are critical in TNF-induced ASK1-JNK/p38 activation.

Received for publication, December 20, 2004 , and in revised form, February 1, 2005.

^* This work was supported by National Institutes of Health Grant HL-65978 (to W. M.). 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.

^|| Established Investigator of the American Heart Association. To whom correspondence should be addressed: Interdepartmental Program in Vascular Biology and Transplantation, Dept. of Pathology, Yale University School of Medicine, BCMM 454, 295 Congress Ave., New Haven, CT 06510. Tel.: 203-785-6047; Fax: 203-737-2293; E-mail: wang.min{at}yale.edu.

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