たんぱく質品質管理に関わる小胞体内の新区画を発見～糖尿病、ALS、アルツハイマー症などに対峙する革新的治療法開発に光～

2025-11-12 東北大学

図1. カルシウム依存的なPDIA6の集合化(相分離)
上図:試験管内実験によるPDIA6の「相分離」現象の発見:PDIA6溶液へのカルシウムの添加によって集合体(液滴)を形成。
下図:細胞内小器官のひとつである小胞体内で観測されたPDIA6の液滴:PDIA6が単体だけでなく集合体としても存在することを世界で初めて発見。

<関連情報>

• https://www.tohoku.ac.jp/japanese/2025/11/press20251112-01-PDI.html
• https://www.tohoku.ac.jp/japanese/newimg/pressimg/tohokuuniv-press20251112_01web_PDI.pdf
• https://www.nature.com/articles/s41556-025-01794-8

Ca 2+駆動PDIA6生体分子凝縮はプロインスリンの折り畳みを確実にする Ca2+-driven PDIA6 biomolecular condensation ensures proinsulin folding

Young-Ho Lee,Tomohide Saio,Mai Watabe,Motonori Matsusaki,Shingo Kanemura,Yuxi Lin,Taro Mannen,Tsubura Kuramochi,Yuka Kamada,Katsuya Iuchi,Michiko Tajiri,Kotono Suzuki,Yan Li,Yunseok Heo,Kotone Ishii,Kenta Arai,Kazunori Ban,Mayuko Hashimoto,Shuichiro Oshita,Satoshi Ninagawa,Yoshikazu Hattori,Hiroyuki Kumeta,Airu Takeuchi,Shinji Kajimoto,… Masaki Okumura
Nature Cell Biology  Published:11 November 2025
DOI:https://doi.org/10.1038/s41556-025-01794-8

Abstract

The endoplasmic reticulum (ER) plays crucial roles in maintaining protein quality control and regulating dynamic Ca²⁺ storage in eukaryotic cells. However, the proteostasis system involved in ER-mediated protein quality control has not been fully characterized. Here we show that Ca²⁺ triggers the condensation of PDIA6, an ER-resident disulfide isomerase and molecular chaperone, into quality control granules. In contrast to the condensation mechanism observed for proteins containing low-complexity domains, our results indicate that transient but specific electrostatic interactions occur between the first and the third folded thioredoxin-like domains of PDIA6. We further show that the PDIA6 condensates recruit proinsulin, thereby accelerating the oxidative proinsulin folding and suppressing the proinsulin aggregation inside quality control granules, essential for secretion of insulin.