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J. Biol. Chem., Vol. 281, Issue 51, 39316-39329, December 22, 2006

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A Multienzyme Network Functions in Intestinal Protein Digestion by a Platyhelminth Parasite^*

Melaine Delcroix, Mohammed Sajid, Conor R. Caffrey, Kee-C. Lim, Jan Dvoák, Ivy Hsieh, Mahmoud Bahgat^¶, Colette Dissous, and James H. McKerrow¹

From the Department of Pathology, Tropical Disease Research Unit and Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, California 94158, Unité 547 Inserm, Institut Pasteur de Lille, 59019 Lille Cedex, France, and ^¶Therapeutical Chemistry Department and Infectious Diseases and Immunology Laboratory, the Road to Nobel Project, The National Research Center, Dokki, Cairo 12311, Egypt

Proteases frequently function not only as individual enzymes but also in cascades or networks. A notable evolutionary switch occurred in one such protease network that is involved in protein digestion in the intestine. In vertebrates, this is largely the work of trypsin family serine proteases, whereas in invertebrates, cysteine proteases of the papain family and aspartic proteases assume the role. Utilizing a combination of protease class-specific inhibitors and RNA interference, we deconvoluted such a network of major endopeptidases functioning in invertebrate intestinal protein digestion, using the parasitic helminth, Schistosoma mansoni as an experimental model. We show that initial degradation of host blood proteins is ordered, occasionally redundant, and substrate-specific. Although inhibition of parasite cathepsin D had a greater effect on primary cleavage of hemoglobin, inhibition of cathepsin B predominated in albumin degradation. Nevertheless, in both cases, inhibitor combinations were synergistic. An asparaginyl endopeptidase (legumain) also synergized with cathepsin B and L in protein digestion, either by zymogen activation or facilitating substrate cleavage. This protease network operates optimally in acidic pH compartments either in the gut lumen or in vacuoles of the intestinal lining cells. Defining the role of each of these major enzymes now provides a clearer understanding of the function of a complex protease network that is conserved throughout invertebrate evolution. It also provides insights into which of these proteases are logical targets for development of chemotherapy for schistosomiasis, a major global health problem.

Received for publication, July 27, 2006 , and in revised form, September 5, 2006.

^* This work was supported by National Institutes of Health Grant AI-053247 and The Sandler Family Supporting 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 Pathology, UC San Francisco, 1700 4th St., San Francisco, CA 94158. Tel.: 415-476-2940; Fax: 415-502-8193; E-mail: jmck{at}cgl.ucsf.edu.

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