Involvement of a novel Q-SNARE, D12, in quality control of the endomembrane system

被引:26
作者
Okumura, AJ
Hatsuzawa, K
Tamura, T
Nagaya, H
Saeki, K
Okumura, F
Nagao, K
Nishikawa, M
Yoshimura, A
Wada, I [1 ]
机构
[1] Fukushima Med Univ, Sch Med, Inst Biomed Sci, Dept Cell Sci, Fukushima 9601295, Japan
[2] Kyushu Univ, Med Inst Bioregulat, Div Mol & Cellular Immunol, Higashi Ku, Fukuoka 8128582, Japan
[3] Kirin Brewery Pharmaceut Res Labs, Takasaki, Gumma 3701295, Japan
关键词
D O I
10.1074/jbc.M509715200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 alpha-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.
引用
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页码:4495 / 4506
页数:12
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