Proteome changes of RPE-1 cells in response to lysosomal damage

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.