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J. Biol. Chem., Vol. 281, Issue 7, 4495-4506, February 17, 2006

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Involvement of a Novel Q-SNARE, D12, in Quality Control of the Endomembrane System^*

Akiko Joo Okumura¹, Kiyotaka Hatsuzawa^¶, Taku Tamura^¶, Hisao Nagaya^¶, Kazuko Saeki, Fumihiko Okumura^||, Kenji Nagao^**, Mitsuo Nishikawa^**, Akihiko Yoshimura, and Ikuo Wada^¶2

From the Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 the ^¶Department of Cell Science, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, the ^||Division of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, ^**Kirin Brewery Pharmaceutical Research Laboratories, 3 Miyahara, Takasaki, Gunma 370-1295, and CREST, JST, Saitama 332-0012, Japan

The cellular endomembrane system requires the proper kinetic balance of synthesis and degradation of its individual components, which is maintained in part by a specific membrane fusion apparatus. In this study, we describe the molecular properties of D12, which was identified from a mouse expression library. This C-terminal anchored membrane protein has sequence similarity to both a yeast soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE), Use1p/Slt1p, and a recently identified human syntaxin 18-binding protein, p31. D12 formed a tight complex with syntaxin 18 as well as Sec22b and bound to -SNAP, indicating that D12 is a SNARE protein. Although the majority of D12 is located in the endoplasmic reticulum and endoplasmic reticulum-Golgi intermediate compartments at steady state, overexpression or knockdown of D12 had no obvious effects on membrane trafficking in the early secretory pathway. However, suppression of D12 expression caused rapid appearance of lipofuscin granules, accompanied by apoptotic cell death without the apparent activation of the unfolded protein response. The typical cause of lipofuscin formation is the impaired degradation of mitochondria by lysosomal degradative enzymes, and, consistent with this, we found that proper post-Golgi maturation of cathepsin D was impaired in D12-deficient cells. This unexpected observation was supported by evidence that D12 associates with VAMP7, a SNARE in the endosomal-lysosomal pathway. Hence, we suggest that D12 participates in the degradative function of lysosomes.

Received for publication, September 2, 2005 , and in revised form, December 7, 2005.

^* This work was supported by special grants-in-aid from the Ministry of Education, Science, Technology, Sports, and Culture of Japan, the Japan Health Science Foundation, the Human Frontier Science Program, the Japan Research Foundation for Clinical Pharmacology, and the Uehara Memorial 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ Supported by the Japan Society for the Promotion of Science.

² To whom correspondence should be addressed: Dept. of Cell Science, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295. Tel.: 81-24-547-1663; Fax: 81-24-549-8898; E-mail: iwada{at}fmu.ac.jp.

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