title: Zinc transport complexes contribute to the homeostatic maintenance of secretory pathway function in vertebrate cells.
abstract: 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.
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Ishihara
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ishida
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kimimitsu
authors.initials: K
authors.lastname: Oda
authors.forename: Masaya
authors.initials: M
authors.lastname: Nagao
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamaguchi-Iwai
authors.forename: Taiho
authors.initials: T
authors.lastname: Kambe
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002645:Chickens; D004268:DNA-Binding Proteins / Q000378:metabolism; D025461:Feedback, Physiological / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D017510:Protein Folding; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D022142:Secretory Vesicles / Q000502:physiology*; D014157:Transcription Factors; D015854:Up-Regulation / Q000502:physiology; D014714:Vertebrates; D000071717:X-Box Binding Protein 1; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; C486753:Slc30a5 protein, mouse; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C472293:ZnT7 protein, mouse; D015032:Zinc