Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
Department of Biochemistry, University of Geneva, Geneva, Switzerland.
Nat Cell Biol. 2021 Mar;23(3):232-242. doi: 10.1038/s41556-021-00644-7. Epub 2021 Mar 8.
Lysosomes must maintain the integrity of their limiting membrane to ensure efficient fusion with incoming organelles and degradation of substrates within their lumen. Pancreatic cancer cells upregulate lysosomal biogenesis to enhance nutrient recycling and stress resistance, but it is unknown whether dedicated programmes for maintaining the integrity of the lysosome membrane facilitate pancreatic cancer growth. Using proteomic-based organelle profiling, we identify the Ferlin family plasma membrane repair factor Myoferlin as selectively and highly enriched on the membrane of pancreatic cancer lysosomes. Mechanistically, lysosomal localization of Myoferlin is necessary and sufficient for the maintenance of lysosome health and provides an early acting protective system against membrane damage that is independent of the endosomal sorting complex required for transport (ESCRT)-mediated repair network. Myoferlin is upregulated in human pancreatic cancer, predicts poor survival and its ablation severely impairs lysosome function and tumour growth in vivo. Thus, retargeting of plasma membrane repair factors enhances the pro-oncogenic activities of the lysosome.
溶酶体必须保持其限膜的完整性，以确保与进入的细胞器有效融合，并降解腔内的底物。胰腺癌细胞上调溶酶体生物发生以增强营养物质的回收和应激抗性，但尚不清楚是否有专门的程序来维持溶酶体膜的完整性，以促进胰腺癌的生长。通过基于蛋白质组学的细胞器分析，我们确定 Ferlin 家族质膜修复因子肌联蛋白（Myoferlin）作为选择性和高度富集在胰腺癌细胞溶酶体膜上的蛋白。从机制上讲，肌联蛋白的溶酶体定位对于溶酶体的健康是必需的和充分的，它提供了一种早期作用的保护系统，防止膜损伤，这种保护系统独立于内体分选复合物所需的运输（ESCRT）介导的修复网络。肌联蛋白在人类胰腺癌中上调，预测预后不良，其缺失严重损害溶酶体功能，并在体内严重损害肿瘤生长。因此，质膜修复因子的重靶向增强了溶酶体的致癌活性。
