Ren Wei-Wei, Kawahara Rebeca, Suzuki Kenichi G N, Dipta Priya, Yang Ganglong, Thaysen-Andersen Morten, Fujita Morihisa
Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, China.
Institute for Glyco-core Research (iGCORE), Gifu University , Gifu, Japan.
J Cell Biol. 2025 Mar 3;224(3). doi: 10.1083/jcb.202407068. Epub 2025 Jan 3.
Many cancer cells exhibit increased amounts of paucimannose glycans, which are truncated N-glycan structures rarely found in mammals. Paucimannosidic proteins are proposedly generated within lysosomes and exposed on the cell surface through a yet uncertain mechanism. In this study, we revealed that paucimannosidic proteins are produced by lysosomal glycosidases and secreted via lysosomal exocytosis. Interestingly, lysosomal exocytosis preferentially occurred in the vicinity of focal adhesions, protein complexes connecting the actin cytoskeleton to the extracellular matrix. Through genome-wide knockout screening, we identified that MYO18B, an actin crosslinker, is required for focal adhesion maturation, facilitating lysosomal exocytosis and the release of paucimannosidic lysosomal proteins to the extracellular milieu. Moreover, a mechanosensitive cation channel PIEZO1 locally activated at focal adhesions imports Ca2+ necessary for lysosome-plasma membrane fusion. Collectively, our study unveiled an intimate relationship between lysosomal exocytosis and focal adhesion, shedding light on the unexpected interplay between lysosomal activities and cellular mechanosensing.
许多癌细胞表现出大量的寡甘露糖聚糖，这是一种在哺乳动物中很少发现的截短型N-聚糖结构。寡甘露糖蛋白据推测是在溶酶体内产生，并通过一种尚不确定的机制暴露在细胞表面。在本研究中，我们揭示寡甘露糖蛋白是由溶酶体糖苷酶产生，并通过溶酶体胞吐作用分泌。有趣的是，溶酶体胞吐作用优先发生在粘着斑附近，粘着斑是将肌动蛋白细胞骨架与细胞外基质连接起来的蛋白质复合物。通过全基因组敲除筛选，我们确定肌动蛋白交联蛋白MYO18B是粘着斑成熟所必需的，它促进溶酶体胞吐作用以及寡甘露糖溶酶体蛋白释放到细胞外环境中。此外，在粘着斑处局部激活的机械敏感阳离子通道PIEZO1会导入溶酶体与质膜融合所需的Ca2+。总的来说，我们的研究揭示了溶酶体胞吐作用与粘着斑之间的密切关系，为溶酶体活动与细胞机械传感之间意想不到的相互作用提供了线索。
