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Proteome changes of RPE-1 cells in response to lysosomal damage with the TAK1 inhibitor

ABSTRACT: The lysosomal damage response plays a critical role in the maintenance of cellular homeostasis. While the repair and autophagic elimination mechanisms of damaged lysosomes have been elucidated, the early signal transduction and subsequent gene expression in response to lysosomal damage remain elusive. Here, we employed transcriptome and proteome analyses to demonstrate that the TAB–TAK1–IKK–NF-κB pathway is activated by K63-linked ubiquitin chains that accumulate on damaged lysosomes. This results in the gene expression of a diverse range of transcription factors and cytokines, which subsequently promote anti-apoptosis and intercellular signaling. These findings indicate that the ubiquitin-directed signal transduction and gene expression play a crucial role in cell survival and cell-cell communication in response to lysosomal damage. The results highlight that the ubiquitin system is involved not only in the removal of damaged lysosomes by lysophagy, but also in the activation of cellular signaling for cell survival.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Htert-rpe1 Cell

SUBMITTER: Akinori Endo

LAB HEAD: Akinori Endo

PROVIDER: PXD058075 | Pride | 2025-08-30

REPOSITORIES: Pride

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Project description:Removal of damaged organelles via the process of selective autophagy constitutes a major form of cellular quality control. 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. Lysosomes themselves are also prone to damage and are degraded through the process of 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 inter-relationships, remain poorly understood, including the role and identity of cargo receptors required for completion of lysophagy. 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 lysosomal proteome remodeling during lysophagy. Among proteins dynamically recruited to damaged lysosomes were ubiquitin-binding autophagic cargo receptors. 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). While the related receptor OPTN can drive damage-dependent lysophagy when overexpressed, cells lacking either OPTN or CALCOCO2 still maintain significant lysophagic flux in HeLa cells. 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. These results identify TAX1BP1 as a central component in the lysophagy pathway and provide a proteomic resource for future studies of the lysophagy process.

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Proteome changes of RPE-1 cells in response to lysosomal damage with the TAK1 inhibitor

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