Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface
Abstract Many secretory enzymes acquire essential zinc ions (Zn2+) in the Golgi complex. ERp44, a chaperone operating in the early secretory pathway, also binds Zn2+ to regulate its client binding and release for the control of protein traffic and homeostasis. Notably, three membrane transporter com...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38397-6 |
| _version_ | 1797801282613805056 |
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| author | Yuta Amagai Momo Yamada Toshiyuki Kowada Tomomi Watanabe Yuyin Du Rong Liu Satoshi Naramoto Satoshi Watanabe Junko Kyozuka Tiziana Anelli Tiziana Tempio Roberto Sitia Shin Mizukami Kenji Inaba |
| author_facet | Yuta Amagai Momo Yamada Toshiyuki Kowada Tomomi Watanabe Yuyin Du Rong Liu Satoshi Naramoto Satoshi Watanabe Junko Kyozuka Tiziana Anelli Tiziana Tempio Roberto Sitia Shin Mizukami Kenji Inaba |
| author_sort | Yuta Amagai |
| collection | DOAJ |
| description | Abstract Many secretory enzymes acquire essential zinc ions (Zn2+) in the Golgi complex. ERp44, a chaperone operating in the early secretory pathway, also binds Zn2+ to regulate its client binding and release for the control of protein traffic and homeostasis. Notably, three membrane transporter complexes, ZnT4, ZnT5/ZnT6 and ZnT7, import Zn2+ into the Golgi lumen in exchange with protons. To identify their specific roles, we here perform quantitative Zn2+ imaging using super-resolution microscopy and Zn2+-probes targeted in specific Golgi subregions. Systematic ZnT-knockdowns reveal that ZnT4, ZnT5/ZnT6 and ZnT7 regulate labile Zn2+ concentration at the distal, medial, and proximal Golgi, respectively, consistent with their localization. Time-course imaging of cells undergoing synchronized secretory protein traffic and functional assays demonstrates that ZnT-mediated Zn2+ fluxes tune the localization, trafficking, and client-retrieval activity of ERp44. Altogether, this study provides deep mechanistic insights into how ZnTs control Zn2+ homeostasis and ERp44-mediated proteostasis along the early secretory pathway. |
| first_indexed | 2024-03-13T04:49:07Z |
| format | Article |
| id | doaj.art-0a6b54fbaf304914b97f48f7636fa4f0 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T04:49:07Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-0a6b54fbaf304914b97f48f7636fa4f02023-06-18T11:19:05ZengNature PortfolioNature Communications2041-17232023-05-0114111810.1038/s41467-023-38397-6Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interfaceYuta Amagai0Momo Yamada1Toshiyuki Kowada2Tomomi Watanabe3Yuyin Du4Rong Liu5Satoshi Naramoto6Satoshi Watanabe7Junko Kyozuka8Tiziana Anelli9Tiziana Tempio10Roberto Sitia11Shin Mizukami12Kenji Inaba13Institute of Multidisciplinary Research for Advanced Materials, Tohoku UniversityDepartment of Chemistry, Graduate School of Science, Tohoku UniversityInstitute of Multidisciplinary Research for Advanced Materials, Tohoku UniversityDepartment of Molecular and Chemical Life Sciences, Graduate School of Life Sciences, Tohoku UniversityDepartment of Chemistry, Faculty of Science, Tohoku UniversityDepartment of Molecular and Chemical Life Sciences, Graduate School of Life Sciences, Tohoku UniversityDepartment of Ecological Developmental Adaptability Life Sciences, Graduate School of Life Sciences, Tohoku UniversityInstitute of Multidisciplinary Research for Advanced Materials, Tohoku UniversityDepartment of Ecological Developmental Adaptability Life Sciences, Graduate School of Life Sciences, Tohoku UniversityDivision of Genetics and Cell Biology, Vita-Salute University, IRCCS Ospedale San RaffaeleDivision of Genetics and Cell Biology, Vita-Salute University, IRCCS Ospedale San RaffaeleDivision of Genetics and Cell Biology, Vita-Salute University, IRCCS Ospedale San RaffaeleInstitute of Multidisciplinary Research for Advanced Materials, Tohoku UniversityInstitute of Multidisciplinary Research for Advanced Materials, Tohoku UniversityAbstract Many secretory enzymes acquire essential zinc ions (Zn2+) in the Golgi complex. ERp44, a chaperone operating in the early secretory pathway, also binds Zn2+ to regulate its client binding and release for the control of protein traffic and homeostasis. Notably, three membrane transporter complexes, ZnT4, ZnT5/ZnT6 and ZnT7, import Zn2+ into the Golgi lumen in exchange with protons. To identify their specific roles, we here perform quantitative Zn2+ imaging using super-resolution microscopy and Zn2+-probes targeted in specific Golgi subregions. Systematic ZnT-knockdowns reveal that ZnT4, ZnT5/ZnT6 and ZnT7 regulate labile Zn2+ concentration at the distal, medial, and proximal Golgi, respectively, consistent with their localization. Time-course imaging of cells undergoing synchronized secretory protein traffic and functional assays demonstrates that ZnT-mediated Zn2+ fluxes tune the localization, trafficking, and client-retrieval activity of ERp44. Altogether, this study provides deep mechanistic insights into how ZnTs control Zn2+ homeostasis and ERp44-mediated proteostasis along the early secretory pathway.https://doi.org/10.1038/s41467-023-38397-6 |
| spellingShingle | Yuta Amagai Momo Yamada Toshiyuki Kowada Tomomi Watanabe Yuyin Du Rong Liu Satoshi Naramoto Satoshi Watanabe Junko Kyozuka Tiziana Anelli Tiziana Tempio Roberto Sitia Shin Mizukami Kenji Inaba Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface Nature Communications |
| title | Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface |
| title_full | Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface |
| title_fullStr | Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface |
| title_full_unstemmed | Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface |
| title_short | Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface |
| title_sort | zinc homeostasis governed by golgi resident znt family members regulates erp44 mediated proteostasis at the er golgi interface |
| url | https://doi.org/10.1038/s41467-023-38397-6 |
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