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

Abstract

Autophagy maintains cellular homeostasis through lysosomal degradation of cytoplasmic components, yet how prolonged autophagy activation reshapes organelle architecture remains poorly understood. Here we identify a previously unrecognized form of endoplasmic reticulum (ER) remodeling induced by chronic mTOR inhibition. This process triggers the formation of autolamellasomes: multilamellar, ER-derived structures that mediate bulk ER degradation. Unlike canonical ER-phagy, autolamellosome biogenesis requires the core autophagy machinery but is independent of known ER-phagy receptors. Cryo-ET, CLEM, and in vitro reconstitution reveal that they arise from autophagy-dependent assembly and compaction of fragmented ER into concentric stacks, which are then engulfed by lysosomes. Autolamellasomes occur at low levels constitutively, but accumulate in senescent cells and HGPS fibroblasts, linking sustained mTOR suppression to aging and ER/lysosomal homeostasis. This work clarifies the origin of intra-lysosomal membrane whorls and introduces a cell-free system for studying autophagy-driven membrane remodeling, connecting nutrient sensing, lipid catabolism, and aging.