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J. Biol. Chem., Vol. 281, Issue 26, 17743-17750, June 30, 2006
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From the
Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan and Division of Biochemistry, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Zinc transporters play important roles in a wide range of biochemical processes. Here we report an important function of ZnT5/ZnT6 hetero-oligomeric complexes in the secretory pathway. The activity of human tissue-nonspecific alkaline phosphatase (ALP) expressed in ZnT5–ZnT7–/– cells was significantly reduced compared with that expressed in wild-type cells as in the case of endogenous chicken tissue-nonspecific ALP activity. The inactive human tissue-nonspecific ALP in ZnT5–ZnT7–/– cells was degraded by proteasome-mediated degradation without being trafficked to the plasma membrane. ZnT5–ZnT7–/– cells showed exacerbation of the unfolded protein response as did the wild-type cells cultured under a zinc-deficient condition, revealing that both complexes play a role in homeostatic maintenance of secretory pathway function. Furthermore, we showed that expression of ZnT5 mRNA was up-regulated by the endoplasmic reticulum stress in various cell lines. The up-regulation of the hZnT5 transcript was mediated by transcription factor XBP1 through the TGACGTGG sequence in the hZnT5 promoter, and this sequence was highly conserved in the ZnT5 genes of mouse and chicken. These results suggest that zinc transport into the secretory pathway is strictly regulated for the homeostatic maintenance of secretory pathway function in vertebrate cells.
Received for publication, March 16, 2005 , and in revised form, April 11, 2006.
* This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to Y. Y.-I. and T. K.) and by Mishima Kaiun Memorial Foundation (to T. K.). 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 nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) DQ382267 [GenBank]
1 Supported by the 21st Century Center of Excellence Program of the Ministry of Education, Culture, Sports, Science, and Technology of Japan to the Graduate School of Biostudies and Institute for Virus Research, Kyoto University.
2 To whom correspondence should be addressed. Tel.: 81-75-753-6273; Fax: 81-75-753-6274; E-mail: kambe1{at}kais.kyoto-u.ac.jp.
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