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J. Biol. Chem., Vol. 282, Issue 18, 13438-13446, May 4, 2007

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Activation of Histidine Decarboxylase through Post-translational Cleavage by Caspase-9 in a Mouse Mastocytoma P-815^*

Kazuyuki Furuta, Kazuhisa Nakayama, Yukihiko Sugimoto, Atsushi Ichikawa, and Satoshi Tanaka^¶1

From the Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan and the Departments of Physiological Chemistry and ^¶Immunobiology, School of Pharmaceutical Science, Mukogawa Women's University, Nishinomiya, Hyogo 663-8179, Japan

L-Histidine decarboxylase (HDC) is the rate-limiting enzyme for histamine synthesis in mammals. Although accumulating evidence has indicated the post-translational processing of HDC, it remains unknown what kinds of proteases are involved. We investigated the processing of HDC in a mouse mastocytoma, P-815, using a lentiviral expression system. HDC was expressed as a 74-kDa precursor form, which is cleaved to yield the 55- and 60-kDa forms upon treatment with butyrate. Alanine-scanning mutations revealed that two tandem aspartate residues (Asp⁵¹⁷-Asp⁵¹⁸, Asp⁵⁵⁰-Asp⁵⁵¹) are critical for the processing. Treatment with butyrate caused an increase in the enzyme activity of the cells expressing the wild type HDC, but not in the cells expressing the processing-incompetent mutant. An increase in histamine synthesis by butyrate was accompanied by formation of the 55- and 60-kDa form of HDC. In addition, the in vitro translated 74-kDa form of HDC was found to undergo a limited cleavage by purified human caspase-9, whereas the alanine-substituted mutants were not. Processing and enzymatic activation of HDC in P-815 cells was enhanced in the presence of a Zn²⁺ chelator, TPEN. Although treatment with butyrate and TPEN drastically augmented the protease activity of caspase-3, and -9, no apoptotic cell death was observed. Both enzymatic activation and processing of HDC were completely suppressed by a pan-caspase inhibitor, partially but significantly by a specific inhibitor for caspase-9, but not by a caspase-3 inhibitor. These results suggest that, in P-815 cells, histamine synthesis is augmented through the post-translational cleavage of HDC, which is mediated by caspase-9.

Received for publication, October 23, 2006 , and in revised form, January 16, 2007.

^* This study was supported by grants-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture, Japan, and the Takeda Science Foundation. 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: Dept. of Immunobiology, School of Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyogo 663-8179, Japan. Tel.: 81-798-45-9958; E-mail: s_tanaka{at}mukogawa-u.ac.jp.

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