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bioRxiv · 10.1101/2025.11.16.688694

Autolamellasomes: An Autophagy-Dependent Parallel Pathway for Bulk ER Degradation and Lysosome Biogenesis

Lu, D.·Zhang, R.·Shi, W.·Zhan, D.·Yang, Y.·Sun, X.·Zhang, H.·Li, Y.·Li, X.·Yu, L.
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Abstract

Lysosomes containing multilamellar membrane whorls are a hallmark of cellular aging and storage disorders, yet the biogenesis of these structures has remained elusive for decades. Here, we identify a distinct form of endoplasmic reticulum (ER) remodeling, termed autolamellasomes, which mediates bulk ER degradation under chronic mTOR inhibition. Unlike canonical ER-phagy, autolamellasomes are concentric ER stacks that form via an autophagy-dependent but receptor-independent mechanism. Using Cryo-ET, CLEM, and a reconstituted cell-free system, we demonstrate that these structures arise from the cytosolic compaction of fragmented ER membranes, driven by the core autophagy machinery. We find that autolamellasomes accumulate in senescent cells and fibroblasts from patients with Hutchinson-Gilford progeria syndrome, linking sustained mTOR suppression to lysosomal membrane homeostasis. Our results resolve the origin of intralysosomal whorls and define a conserved pathway that couples nutrient sensing to membrane turnover and cellular aging.

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Lu, D., Zhang, R., Shi, W., Zhan, D., Yang, Y., Sun, X., Zhang, H., Li, Y., Li, X., Yu, L.. 2025-11-16. Autolamellasomes: An Autophagy-Dependent Parallel Pathway for Bulk ER Degradation and Lysosome Biogenesis. https://doi.org/10.1101/2025.11.16.688694

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