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J. Biol. Chem., Vol. 279, Issue 47, 49497-49507, November 19, 2004

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Rab5-associated Vacuoles Play a Unique Role in Phagocytosis of the Enteric Protozoan Parasite Entamoeba histolytica^*

Yumiko Saito-Nakano, Tomoyoshi Yasuda, Kumiko Nakada-Tsukui, Matthias Leippe, and Tomoyoshi Nozaki¶||

From the Department of Parasitology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan, the Zoologisches Institut der Christian-Albrechts-Universität Kiel, Olshausenstrasse 40, 24118 Kiel, Germany, and the ^¶Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, 2-20-5 Akebono-cho, Tachikawa, Tokyo 190-0012, Japan

In mammals, Rab5 and Rab7 play a specific and coordinated role in a sequential process during phagosome maturation. Here, we report that Rab5 and Rab7 in the enteric protozoan parasite Entamoeba histolytica, EhRab5 and EhRab7A, are involved in steps that are distinct from those known for mammals. EhRab5 and EhRab7A were localized to independent small vesicular structures at steady state. Priming with red blood cells induced the formation of large vacuoles associated with both EhRab5 and EhRab7A ("prephagosomal vacuoles (PPV)") in the amoeba within an incubation period of 5–10 min. PPV emerged de novo physically and distinct from phagosomes. PPV were gradually acidified and matured by fusion with lysosomes containing a digestive hydrolase, cysteine proteinase, and a membrane-permeabilizing peptide amoebapore. After EhRab5 dissociated from PPV, 5–10 min later, the EhRab7A-PPV fused with phagosomes, and EhRab7A finally dissociated from the phagosomes. Immunoelectron and light micrographs showed that PPV contained small vesicle-like structures containing fluid-phase markers and amoebapores, which were not evenly distributed within PPV, suggesting that the mechanism was similar to multivesicular body formation in PPV generation. In contrast to Rab5 from other organisms, EhRab5 was involved exclusively in phagocytosis, but not in endocytosis. Overexpression of wild-type EhRab5 enhanced phagocytosis and the transport of amoebapore to phagosomes. Conversely, expression of an EhRab5Q67L GTP form mutant impaired the formation of PPV and phagocytosis. Altogether, we propose that the amoebic Rab5 plays an important role in the formation of unique vacuoles, which is essential for engulfment of erythrocytes and important for packaging of lysosomal hydrolases, prior to the targeting to phagosomes.

Received for publication, April 4, 2004 , and in revised form, August 27, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB054582 (EhRab5) and AB054583 (EhRab7A).

^* This work was supported in part by a grant for Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Grant-in-aid for Scientific Research 15790219 (to Y. S.-N.) and 15019120 and 15590378 (to T. N.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a grant for Research on Emerging and Re-emerging Infectious Diseases from the Ministry of Health, Labor, and Welfare, a grant for the Project to Promote Development of Anti-AIDS Pharmaceuticals from the Japan Health Sciences Foundation (to T. N.), and a grant from the Deutsche Forschungsgemeinschaft (to M. L.). 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.

^|| To whom all correspondence should be addressed: Dept. of Parasitology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. Tel.: 81-3-5285-1111 (ext. 2733), Fax: 81-3-5285-1173; E-mail: nozaki{at}nih.go.jp and nozaki{at}med.gunma-u.ac.jp.

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