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J. Biol. Chem., Vol. 282, Issue 34, 24806-24815, August 24, 2007

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MARCH-XI, a Novel Transmembrane Ubiquitin Ligase Implicated in Ubiquitin-dependent Protein Sorting in Developing Spermatids^*

Yuri Morokuma, Nobuhiro Nakamura, Akira Kato, Michitaka Notoya, Yoko Yamamoto, Yasuhiro Sakai^¶, Hidekazu Fukuda¹, Shohei Yamashina^¶, Yukio Hirata, and Shigehisa Hirose²

From the Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, Japan, Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan, and the ^¶Department of Anatomy, Kitasato University School of Medicine, Sagamihara 228-8555, Japan

A mechanism by which ubiquitinated cargo proteins are sorted into multivesicular bodies (MVBs) from plasma and trans-Golgi network (TGN) membranes is well established in yeast and mammalian somatic cells. However, the ubiquitin-dependent sorting pathway has not been clearly defined in germ cells. In this study we identified a novel member of the transmembrane RING-finger family of proteins, termed membrane-associated RING-CH (MARCH)-XI, that is expressed predominantly in developing spermatids and weakly in brain and pituitary. MARCH-XI possesses an E3 ubiquitin ligase activity that targets CD4 for ubiquitination. Immunoelectron microscopy of rat round spermatids showed that MARCH-XI is localized to TGN-derived vesicles and MVBs. Fluorescence staining of rat round spermatids and immunoprecipitation of rat testis demonstrated that MARCH-XI forms complexes with the adaptor protein complex-1 and with fucose-containing glycoproteins including ubiquitinated forms. Furthermore, the C-terminal region of MARCH-XI mediates its interaction with µ1-adaptin and Veli through a tyrosine-based motif and a PDZ binding motif, respectively. Our data suggest that MARCH-XI acts as a ubiquitin ligase with a role in ubiquitin-mediated protein sorting in the TGN-MVB transport pathway, which may be involved in mammalian spermiogenesis.

Received for publication, January 16, 2007 , and in revised form, June 11, 2007.

^* This work was supported by the 21st Century Center of Excellence Program and the Grant-in-Aid for Scientific Research 14104002, for Young Scientists 16710145 and 16770144, and for Scientific Research on Priority Areas "Transportsome" 18059010 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material including Figs. S1–S6.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB048841 and AB048842.

¹ Present address: Department of Physiology, Kitasato University School of Medicine, Sagamihara 228-8555, Japan.

² To whom correspondence should be addressed: Dept. of Biological Sciences, Tokyo Institute of Technology, 4259-B-19 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan. Tel.: 81-45-924-5726; Fax: 81-45-924-5824; E-mail: shirose{at}bio.titech.ac.jp.

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