Mechanosensory channels mediate ER Ca²⁺ transients to trigger assembly of autophagosome initiation sites for degradation of ER subdomains

Molecular Cell, 2 April, 2026, DOI：https://doi.org/10.1016/j.molcel.2026.03.002

Mechanosensory channels mediate ER Ca²⁺ transients to trigger assembly of autophagosome initiation sites for degradation of ER subdomains

Xiaoli Ma, Zhiyang Cheng, Hongyu Zhao, Huan Zhang, Ke Xiao, Jiali Xie, Yun Feng, Chun Yang, Yujie Feng, Xi Wang, Yaozu Xiang, Junjie Hu, Qiaoxia Zheng, Wei Ji, Hong Zhang

Abstract

ER-phagy involves the selective autophagosomal engulfment of ER fragments, but the signaling events, selection mechanisms, and membrane source of ER-phagic autophagosomes remain elusive. Here, using state-of-the-art super-resolution multi-SIM imaging, we reveal that stresses (prolonged starvation, cholesterol dyshomeostasis, and high-Ca²⁺ insults) trigger the expansion of sheet ER subdomains containing high levels of luminal Ca²⁺ in mammalian cells, which are subsequently degraded by ER-phagy. Autophagosome formation and sequestration of ER sheets require the concerted actions of FAM134B and lipidated LC3, whereas the autophagy proteins ATG14 and ATG9 are partially dispensable. Electron microscopy and cryo-electron tomography show that the membranes of autophagosomes enclosing high-Ca²⁺-containing ER sheets are directly remodeled from the ER. The ER-localized cation channels PIEZO1 and TRPV1 are enriched at and mediate Ca²⁺ transients from high-Ca²⁺-containing ER sheets, triggering liquid-liquid phase separation of the autophagosome-initiating FIP200 complex to initiate ER-phagy. Thus, distinct mechanisms are employed for the formation of high-Ca²⁺-containing ER-enclosing autophagosomes and non-selective autophagosomes.

文章链接：https://www.sciencedirect.com/science/article/pii/S1097276526001589

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