Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
FEBS Lett. 2020 Jan;594(1):144-152. doi: 10.1002/1873-3468.13581. Epub 2019 Aug 31.
Purinergic signaling plays important roles in bone. P2X5, a member of ligand-gated ion channel receptors, has been demonstrated to regulate osteoclast maturation. However, the molecular mechanism of P2X5-mediated osteoclast regulation remains unclear. Here, we identified methylosome protein 50 (MEP50), a critical cofactor of the protein arginine methyltransferase 5 (PRMT5), as a P2X5-associating molecule. RNAi-mediated knockdown of MEP50 results in decreased formation of mature osteoclasts. MEP50 associates with P2X5, and this association requires the C-terminal intracellular region of P2X5. Additionally, impaired maturation of P2X5-deficient osteoclasts could be restored by transduction of full-length P2X5, but not a C-terminal deletion mutant of P2X5. These results indicate that P2X5 associates with MEP50 and suggest a link between the PRMT5 complex and P2X5 signaling in osteoclast maturation.
嘌呤能信号在骨骼中发挥重要作用。P2X5 是配体门控离子通道受体的成员，已被证明可调节破骨细胞成熟。然而，P2X5 介导的破骨细胞调节的分子机制尚不清楚。在这里，我们鉴定了甲基体蛋白 50（MEP50），一种蛋白质精氨酸甲基转移酶 5（PRMT5）的关键辅助因子，作为 P2X5 相关分子。MEP50 的 RNAi 介导的敲低导致成熟破骨细胞的形成减少。MEP50 与 P2X5 相关联，这种关联需要 P2X5 的胞内 C 末端区域。此外，通过转导全长 P2X5 可以恢复 P2X5 缺陷型破骨细胞的成熟障碍，但不能恢复 P2X5 的 C 末端缺失突变体。这些结果表明 P2X5 与 MEP50 相关联，并提示 PRMT5 复合物与 P2X5 信号在破骨细胞成熟中的联系。
