Cells respond to lysosomal membrane permeabilization by membrane repair or selective macroautophagy of damaged lysosomes, termed lysophagy, but it is not fully understood how this decision is made. Here, we uncover a pathway in human cells that detects lipid bilayer perturbations in the limiting membrane of compromised lysosomes, which fail to be repaired, and then initiates ubiquitin-triggered lysophagy. We find that SPG20 binds the repair factor IST1 on damaged lysosomes and, importantly, integrates that with the detection of damage-associated lipid-packing defects of the lysosomal membrane. Detection occurs via sensory amphipathic helices in SPG20 before rupture of the membrane. If lipid-packing defects are extensive, such as during lipid peroxidation, SPG20 recruits and activates ITCH, which marks the damaged lysosome with lysine-63-linked ubiquitin chains to initiate lysophagy and thus triages the lysosome for destruction. With SPG20 being linked to neurodegeneration, these findings highlight the relevance of a coordinated lysosomal damage response for cellular homeostasis.

细胞通过膜修复或受损溶酶体的选择性巨自噬对溶酶体膜通透性做出反应，称为溶菌作用，但尚不完全了解这一决定是如何做出的。在这里，我们发现了人类细胞中的一条途径，可以检测受损溶酶体限制膜中的脂质双层扰动，该膜无法修复，然后启动泛素触发的溶菌作用。我们发现 SPG20 与受损溶酶体上的修复因子 IST1 结合，重要的是，它将其与溶酶体膜损伤相关的脂质堆积缺陷的检测结合起来。在膜破裂之前，通过 SPG20 中的感觉两亲螺旋进行检测。如果脂质堆积缺陷广泛，例如在脂质过氧化过程中，SPG20 会招募并激活 ITCH，后者用赖氨酸 63 连接的泛素链标记受损的溶酶体，以启动溶菌作用，从而对溶酶体进行分类以进行破坏。由于 SPG20 与神经退行性变有关，这些发现强调了协调的溶酶体损伤反应与细胞稳态的相关性。