Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.
J Cell Sci. 2022 Feb 15;135(4). doi: 10.1242/jcs.259138. Epub 2022 Feb 18.
Cell migration is a complex process underlying physiological and pathological processes such as brain development and cancer metastasis. The autophagy-linked FYVE protein (ALFY; also known as WDFY3), an autophagy adaptor protein known to promote clearance of protein aggregates, has been implicated in brain development and neural migration during cerebral cortical neurogenesis in mice. However, a specific role of ALFY in cell motility and extracellular matrix adhesion during migration has not been investigated. Here, we reveal a novel role for ALFY in the endocytic pathway and in cell migration. We show that ALFY localizes to RAB5- and EEA1-positive early endosomes in a PtdIns(3)P-dependent manner and is highly enriched in cellular protrusions at the leading and lagging edge of migrating cells. We find that cells lacking ALFY have reduced attachment and altered protein levels and glycosylation of integrins, resulting in the inability to form a proper leading edge and loss of directional cell motility.
细胞迁移是一种复杂的过程，涉及生理和病理过程，如大脑发育和癌症转移。自噬相关 FYVE 蛋白（ALFY；也称为 WDFY3）是一种已知促进清除蛋白质聚集体的自噬衔接蛋白，已被牵连到大脑发育和小鼠大脑皮质神经发生过程中的神经迁移。然而，ALFY 在迁移过程中的细胞运动和细胞外基质黏附中的具体作用尚未被研究。在这里，我们揭示了 ALFY 在细胞内吞途径和细胞迁移中的新作用。我们发现，ALFY 以 PtdIns(3)P 依赖的方式定位于 RAB5 和 EEA1 阳性早期内体上，并且在迁移细胞的前缘和后缘的细胞突起中高度富集。我们发现，缺乏 ALFY 的细胞附着减少，整合素的蛋白水平和糖基化发生改变，导致无法形成适当的前缘，并丧失定向细胞迁移能力。
