Lee Young-Ho, Saio Tomohide, Watabe Mai, Matsusaki Motonori, Kanemura Shingo, Lin Yuxi, Mannen Taro, Kuramochi Tsubura, Kamada Yuka, Iuchi Katsuya, Tajiri Michiko, Suzuki Kotono, Li Yan, Heo Yunseok, Ishii Kotone, Arai Kenta, Ban Kazunori, Hashimoto Mayuko, Oshita Shuichiro, Ninagawa Satoshi, Hattori Yoshikazu, Kumeta Hiroyuki, Takeuchi Airu, Kajimoto Shinji, Abe Hiroya, Mori Eiichiro, Muraoka Takahiro, Nakabayashi Takakazu, Akashi Satoko, Okiyoneda Tsukasa, Vendruscolo Michele, Inaba Kenji, Okumura Masaki
Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan.
Biopharmaceutical Research Center, Korea Basic Science Institute, Cheongju, Republic of Korea.
Nat Cell Biol. 2025 Nov;27(11):1952-1964. doi: 10.1038/s41556-025-01794-8. Epub 2025 Nov 11.
The endoplasmic reticulum (ER) plays crucial roles in maintaining protein quality control and regulating dynamic Ca storage in eukaryotic cells. However, the proteostasis system involved in ER-mediated protein quality control has not been fully characterized. Here we show that Ca 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.
内质网（ER）在维持真核细胞中的蛋白质质量控制和调节动态钙储存方面发挥着关键作用。然而，内质网介导的蛋白质质量控制所涉及的蛋白质稳态系统尚未得到充分表征。在这里，我们表明钙触发了PDIA6（一种内质网驻留的二硫键异构酶和分子伴侣）凝聚形成质量控制颗粒。与含有低复杂性结构域的蛋白质所观察到的凝聚机制不同，我们的结果表明，PDIA6的第一个和第三个折叠的硫氧还蛋白样结构域之间发生了短暂但特定的静电相互作用。我们进一步表明，PDIA6凝聚物招募胰岛素原，从而加速氧化胰岛素原折叠并抑制质量控制颗粒内胰岛素原的聚集，这对胰岛素分泌至关重要。
