Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface

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 and Kenji Inaba ()
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Yuta Amagai: Tohoku University
Momo Yamada: Tohoku University
Toshiyuki Kowada: Tohoku University
Tomomi Watanabe: Tohoku University
Yuyin Du: Tohoku University
Rong Liu: Tohoku University
Satoshi Naramoto: Tohoku University
Satoshi Watanabe: Tohoku University
Junko Kyozuka: Tohoku University
Tiziana Anelli: Vita-Salute University, IRCCS Ospedale San Raffaele
Tiziana Tempio: Vita-Salute University, IRCCS Ospedale San Raffaele
Roberto Sitia: Vita-Salute University, IRCCS Ospedale San Raffaele
Shin Mizukami: Tohoku University
Kenji Inaba: Tohoku University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38397-6

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