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J. Biol. Chem., Vol. 279, Issue 18, 19264-19275, April 30, 2004

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Ricin Triggers Apoptotic Morphological Changes through Caspase-3 Cleavage of BAT3^*

Yu-Hauh Wu, Sheue-Fang Shih, and Jung-Yaw Lin

From the Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 10063, Taiwan, Republic of China

Ricin, one of type II ribosomal inactivating proteins, inhibits protein biosynthesis by its RNA N-glycosidase activity. By yeast two-hybrid screening, the human BAT3 (HLA-B-associated transcript 3) was isolated as a ricin A-chain interacting protein. A canonical caspase-3 cleavage site, DEQD¹⁰⁰¹ was found at the C-terminal region of BAT3. Ricin induced the apoptosis by activating caspase-3 and leading to the cleavage of BAT3 at 4 h after treatment while DNA laddering at 24 h. The cleavage is completely inhibited by zDEVD-fmk, a caspase-3 specific inhibitor. In addition, cleavage of BAT3 is blocked in caspase-3-deficient MCF-7 cells, indicating that BAT3 is a novel caspase-3 substrate. Evidence indicates that caspase-3 activated by ricin acts on BAT3 at the caspase cleavage site, DEQD¹⁰⁰¹ to release a C-terminal fragment designated CTF-131. The CTF-131 induces phosphatidylserine exposure, cell rounding, and chromatin condensation as ricin does. Moreover, silencing expression of endogenous BAT3 concomitantly suppresses ricin-induced apoptosis. Together, our results suggest a model that ricin triggers morphological changes of apoptosis by caspase-3-mediated proteolytic activation of BAT3.

Received for publication, July 2, 2003 , and in revised form, February 11, 2004.

^* This work was supported in part by Grant 89-B-FA01-1-4 from the Ministry of Education and Grant NSC-91-2320-B-002-069 from the National Science Council, Republic of China. 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.

Present address: Taiwan Liposome Company, 11F-1, No. 3, Yuan Cyu St., Nankang, Taipei, Taiwan 115.

To whom correspondence should be addressed. Tel.: 886-2-2312-3456 (ext. 8206); Fax: 886-2-2341-5334; E-mail: jylin{at}ha.mc.ntu.edu.tw.

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