Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China.
Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
Sci Adv. 2020 Dec 9;6(50). doi: 10.1126/sciadv.aba5783. Print 2020 Dec.
Organelle transport requires dynamic cytoskeleton remodeling, but whether cytoskeletal dynamics are, in turn, regulated by organelles remains elusive. Here, we demonstrate that late endosomes, a type of prelysosomal organelles, facilitate actin-cytoskeleton remodeling via cytosolic translocation of immature protease cathepsin D (cathD) during microglia migration. After cytosolic translocation, late endosome-derived cathD juxtaposes actin filaments at the leading edge of lamellipodia. Suppressing cathD expression or blocking its cytosolic translocation impairs the maintenance but not the initiation of lamellipodial extension. Moreover, immature cathD balances the activity of the actin-severing protein cofilin to maintain globular-actin (G-actin) monomer pool for local actin recycling. Our study identifies cathD as a key lysosomal molecule that unconventionally contributes to actin cytoskeleton remodeling via cytosolic translocation during adenosine triphosphate-evoked microglia migration.
细胞器运输需要动态的细胞骨架重塑，但细胞骨架的动态是否反过来受到细胞器的调节仍不清楚。在这里，我们证明晚期内体（一种溶酶体前体细胞器）通过细胞质易位促进细胞骨架重塑在小胶质细胞迁移过程中不成熟的组织蛋白酶 D（cathD）。细胞质易位后，晚期内体衍生的 cathD 在片状伪足的前缘与肌动蛋白丝并列。抑制 cathD 的表达或阻断其细胞质易位会损害但不会影响片状伪足延伸的维持。此外，不成熟的 cathD 平衡肌动蛋白丝切割蛋白 cofilin 的活性，以维持局部肌动蛋白回收的球状肌动蛋白（G-actin）单体池。我们的研究确定 cathD 是一种关键的溶酶体分子，它通过三磷酸腺苷诱导的小胶质细胞迁移过程中的细胞质易位，非传统地有助于肌动蛋白细胞骨架重塑。
