Lysosomes represent the terminal compartment for numerous degradative and recycling pathways which makes their integrity crucial for cell homeostasis. However, under certain stress conditions the lysosomal membrane can be ruptured resulting in functional impairment, leakage of lysosomal content and eventually cell death. To cope with lysosomal damage cells developed several defense strategies. Part of this response is a fast and robust ubiquitylation of damaged lysosomes. Recent ubiquitin profiling suggests that ubiquitin might have functions beyond selective autophagy of lysosomes (lysophagy). Since the regulatory functions of ubiquitin as well as the required machinery remain poorly understood, we employed LysoIP-MS and detected the ubiquitin E3 ligase RNF126 at damaged lysosomes. We validated the translocation of RNF126 upon various lysosomal damage modalities in several cell types and defined its recruiting motif. RNF126 depletion results in a robust decrease of damage-induced ubiquitylation at the lysosome and an impaired lysosomal recovery. We performed ubiquitylation site profiling to map potential ubiquitination substrates and confirmed candidates by denaturing IP and subcellular localization analysis. Currently, we are elucidating the functional consequences of RNF126 dependent ubiquitylation events for the regeneration of lysosome function. Overall, this work provides new mechanistic insights into ubiquitin-mediated regulation of the lysosomal damage response.