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

Author

Listed:
  • Satoshi Watanabe

    (Tohoku University)

  • Yuta Amagai

    (Tohoku University)

  • Sara Sannino

    (IRCCS Ospedale San Raffaele
    University of Pittsburgh)

  • 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
    Japan Science and Technology Agency (JST))

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.

Suggested Citation

  • Satoshi Watanabe & Yuta Amagai & Sara Sannino & Tiziana Tempio & Tiziana Anelli & Manami Harayama & Shoji Masui & Ilaria Sorrentino & Momo Yamada & Roberto Sitia & Kenji Inaba, 2019. "Zinc regulates ERp44-dependent protein quality control in the early secretory pathway," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08429-1
    DOI: 10.1038/s41467-019-08429-1
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    Cited by:

    1. 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 Mizu, 2023. "Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Satoshi Watanabe & Yoshiaki Kise & Kento Yonezawa & Mariko Inoue & Nobutaka Shimizu & Osamu Nureki & Kenji Inaba, 2024. "Structure of full-length ERGIC-53 in complex with MCFD2 for cargo transport," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Sayaka Oda & Kazuhiro Nishiyama & Yuka Furumoto & Yohei Yamaguchi & Akiyuki Nishimura & Xiaokang Tang & Yuri Kato & Takuro Numaga-Tomita & Toshiyuki Kaneko & Supachoke Mangmool & Takuya Kuroda & Reish, 2022. "Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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