2025年新着論文 52　分子生命科学分野から論文が発表されました

Ca²⁺-driven PDIA6 biomolecular condensation ensures proinsulin folding

Nat Cell Biol. 2025 Nov;27(11):1952-1964. doi: 10.1038/s41556-025-01794-8. Epub 2025 Nov 11.

Authors

Young-Ho Lee^#^{1 2 3 4 5}, Tomohide Saio^#^6 7, Mai Watabe^#^8 9, Motonori Matsusaki^#^8 10, Shingo Kanemura^#⁸, Yuxi Lin^#¹¹, Taro Mannen^#¹², Tsubura Kuramochi^#^8 9, Yuka Kamada^#¹³, Katsuya Iuchi^8 14, Michiko Tajiri¹⁵, Kotono Suzuki^8 9, Yan Li^11 16, Yunseok Heo¹¹, Kotone Ishii^8 9, Kenta Arai¹⁷, Kazunori Ban¹⁸, Mayuko Hashimoto⁸, Shuichiro Oshita¹⁹, Satoshi Ninagawa^19 20, Yoshikazu Hattori¹⁰, Hiroyuki Kumeta²¹, Airu Takeuchi^8 9, Shinji Kajimoto¹⁸, Hiroya Abe⁸, Eiichiro Mori²², Takahiro Muraoka^8 23, Takakazu Nakabayashi¹⁸, Satoko Akashi¹⁵, Tsukasa Okiyoneda¹³, Michele Vendruscolo²⁴, Kenji Inaba^{8 25 26}, Masaki Okumura^27 28

Affiliations

¹ Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan. mr0505@kbsi.re.kr.
² Biopharmaceutical Research Center, Korea Basic Science Institute, Cheongju, Republic of Korea. mr0505@kbsi.re.kr.
³ Bio-Analytical Science, University of Science and Technology, Daejeon, Republic of Korea. mr0505@kbsi.re.kr.
⁴ Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Republic of Korea. mr0505@kbsi.re.kr.
⁵ Department of Systems Biotechnology, Chung-Ang University, Gyeonggi, Republic of Korea. mr0505@kbsi.re.kr.
⁶ Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan. saio@tokushima-u.ac.jp.
⁷ Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. saio@tokushima-u.ac.jp.
⁸ Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan.
⁹ Department of Molecular and Chemical Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
¹⁰ Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
¹¹ Biopharmaceutical Research Center, Korea Basic Science Institute, Cheongju, Republic of Korea.
¹² College of Life Sciences, Ritsumeikan University, Kusatsu, Japan.
¹³ Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Sanda, Japan.
¹⁴ Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, Tokyo, Japan.
¹⁵ Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
¹⁶ Research Institute of Biomedical and Health Science, Konkuk University, Chungju, Republic of Korea.
¹⁷ Department of Chemistry, School of Science, Tokai University, Hiratsuka, Japan.
¹⁸ Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
¹⁹ Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe, Japan.
²⁰ Biosignal Research Center, Kobe University, Kobe, Japan.
²¹ Faculty of Advanced Life Science, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan.
²² Department of Future Basic Medicine, Nara Medical University, Kashihara, Japan.
²³ Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan.
²⁴ Department of Chemistry, Centre for Misfolding Disease, University of Cambridge, Cambridge, UK.
²⁵ Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
²⁶ Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.
²⁷ Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan. okmasaki@tohoku.ac.jp.
²⁸ Department of Molecular and Chemical Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan. okmasaki@tohoku.ac.jp.

^# Contributed equally.

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.

Conflict of interest statement

Competing interests: E.M. is a CEO of Molmir, Inc. The remaining authors declare no competing interests. A patent (Japanese Patent number NO. 7194403; PDIA6 droplet formation method) has been registered by M.O., M.M., S. Kanemura, T.S. and K. Inaba.

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