Zinc regulates ERp44-dependent protein quality control in the early secretory pathway

Satoshi Watanabe, Yuta Amagai, Sara Sannino, Tiziana Tempio, Tiziana Anelli, Manami Harayama, Shoji Masui, Ilaria Sorrentino, Momo Yamada, Roberto Sitia () and Kenji Inaba ()
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Satoshi Watanabe: Tohoku University
Yuta Amagai: Tohoku University
Sara Sannino: IRCCS Ospedale San Raffaele
Tiziana Tempio: IRCCS Ospedale San Raffaele
Tiziana Anelli: IRCCS Ospedale San Raffaele
Manami Harayama: Tohoku University
Shoji Masui: Tohoku University
Ilaria Sorrentino: IRCCS Ospedale San Raffaele
Momo Yamada: Tohoku University
Roberto Sitia: IRCCS Ospedale San Raffaele
Kenji Inaba: Tohoku University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Zinc ions (Zn2+) are imported into the early secretory pathway by Golgi-resident transporters, but their handling and functions are not fully understood. Here, we show that Zn2+ binds with high affinity to the pH-sensitive chaperone ERp44, modulating its localization and ability to retrieve clients like Ero1α and ERAP1 to the endoplasmic reticulum (ER). Silencing the Zn2+ transporters that uptake Zn2+ into the Golgi led to ERp44 dysfunction and increased secretion of Ero1α and ERAP1. High-resolution crystal structures of Zn2+-bound ERp44 reveal that Zn2+ binds to a conserved histidine-cluster. The consequent large displacements of the regulatory C-terminal tail expose the substrate-binding surface and RDEL motif, ensuring client capture and retrieval. ERp44 also forms Zn2+-bridged homodimers, which dissociate upon client binding. Histidine mutations in the Zn2+-binding sites compromise ERp44 activity and localization. Our findings reveal a role of Zn2+ as a key regulator of protein quality control at the ER-Golgi interface.

Date: 2019
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DOI: 10.1038/s41467-019-08429-1

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