Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Department of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan.
Sci Rep. 2017 Mar 16;7:41710. doi: 10.1038/srep41710.
Osteoclasts degrade bone matrix proteins via the secretion of lysosomal enzymes. However, the precise mechanisms by which lysosomal components are transported and fused to the bone-apposed plasma membrane, termed ruffled border membrane, remain elusive. Here, we identified coronin 1A as a negative regulator of exocytotic release of cathepsin K, one of the most important bone-degrading enzymes in osteoclasts. The modulation of coronin 1A expression did not alter osteoclast differentiation and extracellular acidification, but strongly affected the secretion of cathepsin K and osteoclast bone-resorption activity, suggesting the coronin 1A-mediated regulation of lysosomal trafficking and protease exocytosis. Further analyses suggested that coronin 1A prevented the lipidation-mediated sorting of the autophagy-related protein LC3 to the ruffled border and attenuated lysosome-plasma membrane fusion. In this process, the interactions between coronin 1A and actin were crucial. Collectively, our findings indicate that coronin 1A is a pivotal component that regulates lysosomal fusion and the secretion pathway in osteoclast-lineage cells and may provide a novel therapeutic target for bone diseases.
破骨细胞通过分泌溶酶体酶来降解骨基质蛋白。然而，溶酶体成分如何被运输并融合到与骨相贴的质膜（称为皱襞缘膜）中，其确切机制仍不清楚。在这里，我们鉴定出冠蛋白 1A 是组织蛋白酶 K 胞吐释放的负调节剂，组织蛋白酶 K 是破骨细胞中最重要的骨降解酶之一。冠蛋白 1A 表达的调节不改变破骨细胞的分化和细胞外酸化，但强烈影响组织蛋白酶 K 的分泌和破骨细胞的骨吸收活性，表明冠蛋白 1A 介导的溶酶体运输和蛋白酶胞吐作用的调节。进一步的分析表明，冠蛋白 1A 阻止了自噬相关蛋白 LC3 的脂化分选到皱襞缘，并减弱了溶酶体-质膜融合。在这个过程中，冠蛋白 1A 与肌动蛋白之间的相互作用至关重要。总的来说，我们的研究结果表明，冠蛋白 1A 是调节破骨细胞系细胞溶酶体融合和分泌途径的关键组成部分，可能为骨疾病提供新的治疗靶点。
