Torsins Organize CLCC1 Assembly to Safeguard ER Bilayer and Lipid Homeostasis

Wang, Y.; Wang, R.; Yao, Y.; Hou, R.; Lu, Y.; Lin, Y.; Hu, Y.; Li, Y.; Wu, L.; Zhu, Y.; Gao, N.; Song, C.; Wang, X.; Ji, Z.; Chen, X.-W.

doi:10.64898/2025.12.14.694184

bioRxiv · 10.64898/2025.12.14.694184

Torsins Organize CLCC1 Assembly to Safeguard ER Bilayer and Lipid Homeostasis

Wang, Y.·Wang, R.·Yao, Y.·Hou, R.·Lu, Y.·Lin, Y.·Hu, Y.·Li, Y.·Wu, L.·Zhu, Y.·Gao, N.·Song, C.·Wang, X.·Ji, Z.·Chen, X.-W.

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Abstract

The TMEM41B scramblase and its regulatory partner CLCC1 initiate lipid flux by equilibrating newly-synthesized phospholipids across the endoplasmic reticulum (ER) bilayer, a fundamental process required for diverse events ranging from membrane biogenesis to bulk lipid supply. Loss of CLCC1/TMEM41B causes ER bilayer imbalance, inducing giant ER-enclosed lipid droplets (geLDs) and driving rapid progression into severe MASH. Here we identify CLCC1 as the long-missing client of the lumenal Torsin ATPases, which selectively engage oligomerized CLCC1 at sites of ER bilayer imbalance. Hepatic TorsinA inactivation triggers geLD formation amid disrupted lipoprotein biogenesis and severe MASH, closely phenocopying CLCC1/TMEM41B deficiency. Mechanistically, Torsins act as foldases that drive CLCC1 oligomerization for its recruitment to imbalanced bilayers. Remarkably, ectopic CLCC1 expression reverses cellular and systemic lipid disorders arising from hepatic TorsinA deficiency. Hence, Torsin ATPases emerge as fundamental regulators that organizes CLCC1 and the downstream TMEM41B scramblase to govern lipid partitioning and membrane homeostasis.

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Wang, Y., Wang, R., Yao, Y., Hou, R., Lu, Y., Lin, Y., Hu, Y., Li, Y., Wu, L., Zhu, Y., Gao, N., Song, C., Wang, X., Ji, Z., Chen, X.-W.. 2025-12-16. Torsins Organize CLCC1 Assembly to Safeguard ER Bilayer and Lipid Homeostasis. https://doi.org/10.64898/2025.12.14.694184

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