Wang Yingxue, Jefferson Matthew, Ramos Maria, Whelband Matthew, Kreuzer Kristin, Khuu Grace, Lazarou Michael, Mccoll James, Lazenby James, Whitchurch Cynthia B, Verkade Paul, Mayer Ulrike, Wileman Thomas
Norwich Medical School, University of East Anglia, Norwich, UK.
Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Autophagy Rep. 2025 May 30;4(1):2476218. doi: 10.1080/27694127.2025.2476218. eCollection 2025.
Hydrolytic enzymes within lysosomes maintain cell and tissue homoeostasis by degrading macromolecules delivered by endocytosis and autophagy. The release of lysosomal enzymes into the cytosol can induce apoptosis and "lysosome-dependent cell death" making it important for damaged lysosomes to be repaired or removed. Extensive lysosome damage exposes luminal sugars to galectin-dependent autophagy pathways that use ATG16L1:ATG5-ATG12 complex to conjugate LC3/ATG8 to autophagosomes to facilitate removal by lysophagy. Sphingomyelin exposed on stressed lysosomes recruits the lysosome tethering protein TECPR1 (tectonin beta propeller repeat-containing protein) allowing an alternative TECRP1:ATG5-ATG12 complex to conjugate LC3 directly to lysosomes. Here we have used cells lacking ATG16L1 to follow the recruitment of TECPR1, galectin-3 and LC3/ATG8 to lysosomes in response to osmotic imbalance induced by chloroquine. TECPR1 was recruited to swollen lysosomes that exposed sphingomyelin. LC3II was absent from swollen lysosomes but located to small puncta that contained the V-ATPase and LAMP1. The presence of galectin-3 and PI4P in the small LC3 puncta suggested that the TECPR1:ATG5-ATG12 complex conjugates LC3 to lysosome remnants that have ruptured in response to osmotic imbalance.
溶酶体内的水解酶通过降解内吞作用和自噬作用传递的大分子来维持细胞和组织的稳态。溶酶体酶释放到细胞质中可诱导细胞凋亡和“溶酶体依赖性细胞死亡”，因此修复或清除受损的溶酶体非常重要。广泛的溶酶体损伤会使腔内糖类暴露于半乳糖凝集素依赖性自噬途径，该途径利用ATG16L1:ATG5-ATG12复合物将LC3/ATG8与自噬体结合，以促进通过溶酶体自噬进行清除。应激溶酶体上暴露的鞘磷脂会招募溶酶体拴系蛋白TECPR1（含tectoninβ螺旋桨重复序列的蛋白），使另一种TECRP1:ATG5-ATG12复合物直接将LC3与溶酶体结合。在这里，我们使用缺乏ATG16L1的细胞来追踪TECPR1、半乳糖凝集素-3和LC3/ATG8响应氯喹诱导的渗透压失衡而向溶酶体的募集情况。TECPR1被募集到暴露鞘磷脂的肿胀溶酶体上。LC3II在肿胀的溶酶体中不存在，但位于含有V-ATP酶和LAMP1的小斑点处。小LC3斑点中半乳糖凝集素-3和PI4P的存在表明，TECPR1:ATG5-ATG12复合物将LC3与因渗透压失衡而破裂的溶酶体残余物结合。
