Regulation of mitochondrial fission by GIPC-mediated Drp1 retrograde transport.
Regulation of mitochondrial fission by GIPC-mediated Drp1 retrograde transport.
复制标题
DOI：
10.1091/mbc.e21-06-0286
复制
发表时间：
2022-01-01
影响因子：
3.3
通讯作者：
Lee NY
中科院分区：
文献类型：
--
作者：
Ramonett A;Kwak EA;Ahmed T;Flores PC;Ortiz HR;Lee YS;Vanderah TW;Largent-Milnes T;Kashatus DF;Langlais PR;Mythreye K;Lee NY
动力蛋白相关蛋白1(Dynamin-Related Protein 1，Drp1)是线粒体分裂的关键调节因子，是一种大的细胞质GTP酶，通过跨膜适配器募集到线粒体表面，启动分裂。虽然布朗运动可能解释了Drp1和线粒体接头之间的局部相互作用，但这种重要的酶是如何从更远的区域(如细胞外围)靶向的仍不清楚。基于蛋白质组相互作用组筛选和基于细胞的研究，我们报道了GAIP/RGS19相互作用蛋白(GIPC)介导了基于肌动蛋白的Drp1向核周线粒体的逆行运输以促进分裂。Drp1通过其非典型的C-末端PDZ结合基序与GIPC相互作用。这种相互作用的丧失会取消Drp1的逆行运输，导致细胞质错误定位和减少分裂，尽管保留了正常的固有GTPase活性。在功能上，我们证明GIPC增强了DRp1驱动的癌细胞的增殖和迁移能力。总之，这些发现在癌症进展和代谢紊乱中GIPC表达的改变和Drp1功能之间建立了直接的分子联系。
Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission, a large cytoplasmic GTPase recruited to the mitochondrial surface via transmembrane adaptors to initiate scission. While Brownian motion likely accounts for the local interactions between Drp1 and the mitochondrial adaptors, how this essential enzyme is targeted from more distal regions like the cell periphery remains unknown. Based on proteomic interactome screening and cell-based studies, we report that GAIP/RGS19-interacting protein (GIPC) mediates the actin-based retrograde transport of Drp1 toward the perinuclear mitochondria to enhance fission. Drp1 interacts with GIPC through its atypical C-terminal PDZ-binding motif. Loss of this interaction abrogates Drp1 retrograde transport resulting in cytoplasmic mislocalization and reduced fission despite retaining normal intrinsic GTPase activity. Functionally, we demonstrate that GIPC potentiates the Drp1-driven proliferative and migratory capacity in cancer cells. Together, these findings establish a direct molecular link between altered GIPC expression and Drp1 function in cancer progression and metabolic disorders.