Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate

Zhenhua Wang, Jingjing He, Yufan Yang, Yonglin He and Hongwu Qian ()
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Zhenhua Wang: University of Science and Technology of China
Jingjing He: University of Science and Technology of China
Yufan Yang: University of Science and Technology of China
Yonglin He: University of Science and Technology of China
Hongwu Qian: University of Science and Technology of China

Nature Communications, 2025, vol. 16, issue 1, 1-8

Abstract: Abstract The lysosome serves as an essential nutrient-sensing hub within the cell, where the mechanistic target of rapamycin complex 1 (mTORC1) is activated. Lysosomal cholesterol signaling (LYCHOS), a lysosome membrane protein, has been identified as a cholesterol sensor that couples cholesterol concentration to mTORC1 activation. However, the molecular basis is unknown. Here, we determine the cryo-electron microscopy (cryo-EM) structure of human LYCHOS at a resolution of 3.1 Å, revealing a cholesterol-like density at the interface between the permease and G-protein coupled receptor (GPCR) domains. Advanced 3D classification reveals two distinct states of LYCHOS. Comparative structural analysis between these two states demonstrated a cholesterol-related movement of GPCR domain relative to permease domain, providing structural insights into how LYCHOS senses lysosomal cholesterol levels. Additionally, we identify indoxyl sulfate (IS) as a binding ligand to the permease domain, confirmed by the LYCHOS-IS complex structure. Overall, our study provides a foundation and indicates additional directions for further investigation of the essential role of LYCHOS in the mTORC1 signaling pathway.

Date: 2025
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DOI: 10.1038/s41467-025-58087-9

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