Center of Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, Essen, Germany.
Munich Cluster for Systems Neurology, Medical Faculty, Ludwig-Maximilians-University München, Munich, Germany.
Mol Cell. 2024 Apr 18;84(8):1556-1569.e10. doi: 10.1016/j.molcel.2024.02.029. Epub 2024 Mar 18.
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（称为溶酶体噬）来响应溶酶体膜通透性增加，但尚不完全清楚细胞如何做出这种选择。在这里，我们在人类细胞中发现了一条途径，该途径可检测到受损溶酶体的限制膜中脂质双层的扰动，这些溶酶体无法被修复，然后引发泛素触发的溶酶体噬作用。我们发现 SPG20 结合 IST1 在受损溶酶体上的修复因子，并且重要的是，将其与溶酶体膜损伤相关的脂质包装缺陷的检测相结合。在膜破裂之前，通过 SPG20 中的感觉两亲性螺旋进行检测。如果脂质包装缺陷广泛，例如在脂质过氧化期间，SPG20 招募并激活 ITCH，ITCH 用赖氨酸 63 连接的泛素链标记受损的溶酶体，以启动溶酶体噬作用，从而将溶酶体分类进行破坏。由于 SPG20 与神经退行性疾病有关，这些发现强调了协调的溶酶体损伤反应对于细胞内稳态的重要性。
