浙江大学孙启明课题组近日取得一项新成果。经过不懈努力，他们的研究开发出了SCAP-FAM134B复合物对胆固醇的感知调节er吞噬和STING先天免疫。2025年10月13日出版的《自然—细胞生物学》杂志发表了这项成果。

本研究表明，ER吞噬受体FAM134B直接与胆固醇和SCAP相互作用，SCAP是胆固醇生物合成的关键调节因子。当内质网胆固醇高时，FAM134B和SCAP通过胆固醇收紧相互作用被隔离，阻止内质网吞噬、STING激活和胆固醇合成。在低胆固醇条件下，FAM134B与SCAP分离，允许SCAP激活SREBP2并上调胆固醇合成，而FAM134B通过寡聚化促进er吞噬或帮助STING运输激活先天免疫反应。这些发现表明，SCAP-FAM134B复合体感知内质网胆固醇水平，调节内质网吞噬和免疫信号，与胆固醇失衡相关的疾病有关。

据了解，内质网（ER）是胆固醇生物合成和运输的核心，但矛盾的是，它维持低胆固醇水平，使其能够感知影响各种信号通路的波动。然而，内质网胆固醇在细胞信号传导中的作用尚不清楚。

附：英文原文

Title: Cholesterol sensing by the SCAP–FAM134B complex regulates ER-phagy and STING innate immunity

Author: Li, Boran, Zhou, Dongheng, Wang, Xinyi, Jiang, Xiao, Sang, Yongjuan, Dai, Youjing, Yao, Yu, Zhang, Yi, Chen, Chen, Li, Shulin, Ni, Wang, Zhou, Quan, Lin, Aifu, Hu, Xinyang, Ge, Liang, Wu, Zhiying, Xu, Pinglong, Neculai, Dante, Liu, Wei, Sun, Qiming

Issue&Volume: 2025-10-13

Abstract: The endoplasmic reticulum (ER) is central to cholesterol biosynthesis and trafficking, yet paradoxically maintains low cholesterol levels, enabling it to sense fluctuations that impact various signalling pathways. However, the role of ER cholesterol in cellular signalling remains unclear. Here we show that the ER-phagy receptor FAM134B interacts directly with both cholesterol and SCAP, a key regulator of cholesterol biosynthesis. When ER cholesterol is high, FAM134B and SCAP are sequestered by cholesterol-tightened interactions, halting ER-phagy, STING activation and cholesterol synthesis. Under low cholesterol conditions, FAM134B dissociates from SCAP, allowing SCAP to activate SREBP2 and upregulate cholesterol synthesis, while FAM134B either facilitates ER-phagy through oligomerization or aids STING trafficking to activate innate immune responses. These findings reveal that the SCAP–FAM134B complex senses ER cholesterol levels, regulating both ER-phagy and immune signalling, with implications for diseases linked to cholesterol imbalance.

DOI: 10.1038/s41556-025-01766-y

Source: https://www.nature.com/articles/s41556-025-01766-y