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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年10月13日

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

摘要

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.