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J. Biol. Chem., Vol. 282, Issue 28, 20553-20560, July 13, 2007

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Heat Shock Protein 75 (TRAP1) Antagonizes Reactive Oxygen Species Generation and Protects Cells from Granzyme M-mediated Apoptosis^*

From the National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China

Natural killer (NK) cells play an important role in innate immunity against virally infected or transformed cells as the first defense line. Granzyme M (GzmM) is an orphan granzyme that is constitutively highly expressed in NK cells and is consistent with NK cell-mediated cytolysis. We recently demonstrated that GzmM induces caspase-dependent apoptosis with DNA fragmentation through direct cleavage of inhibitor of caspase-activated DNase (ICAD). However, the molecular mechanisms for GzmM-induced apoptosis are unclear. We found GzmM causes mitochondrial swelling and loss of mitochondrial transmembrane potential. Moreover, GzmM initiates reactive oxygen species (ROS) generation and cytochrome c release. Heat shock protein 75 (HSP75, also known as TRAP1) acts as an antagonist of ROS and protects cells from GzmM-mediated apoptosis. GzmM cleaves TRAP1 and abolishes its antagonistic function to ROS, resulting in ROS accumulation. Silencing TRAP1 through RNA interference increases ROS accumulation, whereas TRAP1 overexpression attenuates ROS production. ROS accumulation is in accordance with the release of cytochrome c from mitochondria and enhances GzmM-mediated apoptosis.

Received for publication, April 16, 2007 , and in revised form, May 18, 2007.

^* The work was supported by the National Natural Science Foundation of China Program 30470365 (to Z. F.) and the Outstanding Youth Grant (to Z. F.) (30525005), Grants from the 973 Programs (2006CB504303; 2006CB910901), The Hundred Talents Program, and the Knowledge Innovation Program of CAS (KSCX2-YW-R-42) (to Z. F.). 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 should be addressed: National Laboratory of Biomacromolecules and Center for Infection and Immunity, Inst. of Biophysics, Chinese Academy of Sciences, 15 Datun Rd., Beijing 100101, China. Tel.: 010-64888457; Fax: 010-64871293; E-mail: fanz{at}moon.ibp.ac.cn.

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