National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
School of Life Sciences, Tsinghua University, Beijing, China.
J Cell Biol. 2022 Jul 4;221(7). doi: 10.1083/jcb.202201020. Epub 2022 May 16.
Multivesicular bodies (MVBs) contain intralumenal vesicles that are delivered to lysosomes for degradation or released extracellularly for intercellular signaling. Here, we identified Caenorhabditis elegans filamin FLN-2 as a novel regulator of MVB biogenesis. FLN-2 co-localizes with V-ATPase subunits on MVBs, and the loss of FLN-2 affects MVB biogenesis, reducing the number of MVBs in C. elegans hypodermis. FLN-2 associates with actin filaments and is required for F-actin organization. Like fln-2(lf) mutation, inactivation of the V0 or V1 sector of V-ATPase or inhibition of actin polymerization impairs MVB biogenesis. Super-resolution imaging shows that FLN-2 docks V-ATPase-decorated MVBs onto actin filaments. FLN-2 interacts via its calponin-homology domains with F-actin and the V1-E subunit, VHA-8. Our data suggest that FLN-2 mediates the docking of MVBs on the actin cytoskeleton, which is required for MVB biogenesis.
多泡体 (MVBs) 包含腔内囊泡，这些囊泡被递送到溶酶体进行降解，或释放到细胞外进行细胞间信号传递。在这里，我们鉴定出秀丽隐杆线虫的肌联蛋白 FLN-2 是 MVB 生物发生的新调节剂。FLN-2 与 MVB 上的 V-ATPase 亚基共定位，而 FLN-2 的缺失会影响 MVB 的生物发生，减少线虫下皮层中的 MVB 数量。FLN-2 与肌动蛋白丝相关，并且是肌动蛋白丝组织所必需的。与 fln-2(lf) 突变一样，V-ATPase 的 V0 或 V1 区的失活或肌动蛋白聚合的抑制都会损害 MVB 的生物发生。超分辨率成像显示，FLN-2 将 V-ATPase 修饰的 MVB 停靠在肌动蛋白丝上。FLN-2 通过其钙调蛋白同源结构域与肌动蛋白和 V1-E 亚基 VHA-8 相互作用。我们的数据表明，FLN-2 介导 MVB 与肌动蛋白细胞骨架的对接，这是 MVB 生物发生所必需的。
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