As such, mechanisms have evolved to both repair specific types of membrane damage or in some circumstances promote degradation of the damaged organelle by a process referred to as lysophagy ( Maejima et al., 2013 Papadopoulos and Meyer, 2017 Papadopoulos et al., 2020 Yim and Mizushima, 2020). Processes that lead to damaged lysosomal membranes-including physiological and pathophysiological pathways-can promote loss of the appropriate pH gradient and defective proteostasis. A central element in lysosomal function is the acidification of the organelle during maturation, which promotes the activation of luminal proteolytic enzymes. ![]() Third, the lysosome serves as a platform for sensing intracellular (cytosolic and intralysosomal) amino acid availability through regulation of the MTOR–MLST8–RPTOR complex by the Ragulator complex on the lysosomal membrane, including amino acids from both endocytic and autophagic pathways ( Saxton and Sabatini, 2017). Closed autophagosomes then fuse with lysosomes, thereby delivering their cargo to the lysosomal lumen for degradation ( Yim and Mizushima, 2020). ![]() In this process, double membrane structures called autophagosomes are built around cargo through a multistep process, culminating in the closure of the autophagosome around the cargo. Second, lysosomes are the terminal receptacle for a form of protein and organelle turnover called autophagy. First, lysosomes play key roles in the degradation and recycling of proteins delivered from the endocytic, phagocytic, and secretory/biosynthetic pathways. The lysosome-a membrane-bound compartment containing proteolytic enzymes-has several indispensable functions in eukaryotic cells, including a central role in protein homeostasis ( Perera and Zoncu, 2016 Saftig and Puertollano, 2021). These results identify TAX1BP1 as a central component in the lysophagy pathway and provide a proteomic resource for future studies of the lysophagy process. Mechanistically, TAX1BP1-driven lysophagy requires its N-terminal SKICH domain, which binds both TBK1 and the autophagy regulatory factor RB1CC1, and requires upstream ubiquitylation events for efficient recruitment and lysophagic flux. While the related receptor Optineurin (OPTN) can drive damage-dependent lysophagy when overexpressed, cells lacking either OPTN or CALCOCO2 still maintain significant lysophagic flux in HeLa cells. Using newly developed lysophagic flux reporters including Lyso-Keima, we demonstrate that TAX1BP1, together with its associated kinase TBK1, are both necessary and sufficient to promote lysophagic flux in both HeLa cells and induced neurons (iNeurons). Among the proteins dynamically recruited to damaged lysosomes were ubiquitin-binding autophagic cargo receptors. Here, we employ quantitative organelle capture and proximity biotinylation proteomics of autophagy adaptors, cargo receptors, and galectins in response to acute lysosomal damage, thereby revealing the landscape of lysosome-associated proteome remodeling during lysophagy. While early steps involve recognition of ruptured lysosomal membranes by glycan-binding galectins and ubiquitylation of transmembrane lysosomal proteins, many steps in the process, and their interrelationships, remain poorly understood, including the role and identity of cargo receptors required for completion of lysophagy. Lysosomes themselves are also prone to damage and are degraded through the process of lysophagy. Damaged organelles are recognized by a dedicated surveillance machinery, leading to the assembly of an autophagosome around the damaged organelle, prior to fusion with the degradative lysosomal compartment. ![]() Removal of damaged organelles via the process of selective autophagy constitutes a major form of cellular quality control.
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