タンパク質凝集の主要因として細胞内極性を特定 (Scientists Identify Subcellular Polarity as Key Factor in Protein Aggregation)

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2026-03-08 中国科学院(CAS)

中国科学院生物物理研究所のWANG Lei研究チームは、細胞内小器官の極性(polarity)と分子混雑度を定量的に測定し、タンパク質凝集との関係を明らかにした。極性応答プローブをHaloタンパク質で各細胞区画に局在化させ、細胞内環境を比較した結果、小胞体(ER)内部は細胞質よりも高い極性と高い分子混雑度を持つことが判明した。また、ハンチンチン遺伝子由来のpolyQタンパク質は、極性の高いER内では凝集しにくいことが示された。高張処理により極性が低下すると凝集が増加したことから、タンパク質凝集には分子混雑度よりも極性が重要な要因である可能性が示唆された。研究は、タンパク質恒常性や神経変性疾患の理解に新たな視点を提供する。

タンパク質凝集の主要因として細胞内極性を特定 (Scientists Identify Subcellular Polarity as Key Factor in Protein Aggregation)
Schematic diagram of the model for polarity-regulated protein condensate and aggregate formation (Image by WANG Lei’s group)

<関連情報>

ヒト細胞において、小胞体は高い極性を示し、タンパク質凝集は少ない The endoplasmic reticulum displays high polarity with low protein aggregation in human cells

Xinwei Hu,Junlin Chen,Ping Liu,Huaiyue Zhang,Yu Liu,Xin Zhang & Lei Wang
Communications Biology  Published:03 February 2026
DOI:https://doi.org/10.1038/s42003-025-09491-w

Abstract

Many physicochemical properties in the cellular milieu are important for cell function and survival. However, the polarity of different subcellular compartments and its role in protein condensate and aggregate formation within cells are less characterized. Here, we develop a method to compare the polarity in different subcellular compartments using the same polarity-sensitive solvatochromic fluorescent probe. Unexpectedly, the endoplasmic reticulum (ER) lumen displays a higher polarity and a more crowded environment than the cytosol in human cells. Polarity-decreasing and crowding-increasing hypertonic conditions induce condensate or aggregate formation of two intrinsically disordered proteins, with-no-lysine kinase 1 and Huntingtin gene (Htt) exon1 with an expanded polyQ stretch (Htt-polyQ), in the cytosol. However, targeting Htt-polyQ to the ER prevents its aggregation, suggesting that polarity but not crowding is more relevant to protein aggregation. Our results reveal the heterogeneity in subcellular polarity and crowding, and uncover previously unrecognized high-polarity in the ER lumen, which provides a unique environment for maintaining robust proteostasis.

生物化学工学
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