Sharma Amit, Dagar Sunayana, Mylavarapu Sivaram V S
Laboratory of Cellular Dynamics, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone Faridabad-Gurgaon Expressway, Faridabad, Haryana 121001, India.
Affiliated to the Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
J Cell Sci. 2020 Jun 23;133(12):jcs239673. doi: 10.1242/jcs.239673.
The molecular motor dynein is essential for mitotic spindle orientation, which defines the axis of cell division. The light intermediate chain subunits, LIC1 and LIC2, define biochemically and functionally distinct vertebrate dynein complexes, with LIC2-dynein playing a crucial role in ensuring spindle orientation. We reveal a novel, mitosis-specific interaction of LIC2-dynein with the cortical actin-bundling protein transgelin-2. Transgelin-2 is required for maintaining proper spindle length, equatorial metaphase chromosome alignment, spindle orientation and timely anaphase onset. We show that transgelin-2 stabilizes the cortical recruitment of LGN-NuMA, which together with dynein is required for spindle orientation. The opposing actions of transgelin-2 and LIC2-dynein maintain optimal cortical levels of LGN-NuMA. In addition, we show that the highly conserved serine 194 phosphorylation of LIC2 is required for proper spindle orientation, by maintaining mitotic centrosome integrity to ensure optimal astral microtubule nucleation. The work reveals two specific mechanisms through which LIC2-dynein regulates mitotic spindle orientation; namely, through a new interactor transgelin-2, which is required for engagement of LGN-NuMA with the actin cortex, and through mitotic phosphoregulation of LIC2 to control microtubule nucleation from the poles.This article has an associated First Person interview with the first author of the paper.
分子马达动力蛋白对于有丝分裂纺锤体定向至关重要，而纺锤体定向决定了细胞分裂的轴。轻中间链亚基LIC1和LIC2在生化和功能上定义了不同的脊椎动物动力蛋白复合物，其中LIC2-动力蛋白在确保纺锤体定向中起关键作用。我们揭示了LIC2-动力蛋白与皮质肌动蛋白成束蛋白转胶蛋白-2之间一种新的、有丝分裂特异性的相互作用。维持适当的纺锤体长度、赤道中期染色体排列、纺锤体定向和及时进入后期都需要转胶蛋白-2。我们表明，转胶蛋白-2可稳定LGN-NuMA在皮质的募集，而纺锤体定向需要LGN-NuMA与动力蛋白共同作用。转胶蛋白-2和LIC2-动力蛋白的相反作用维持了LGN-NuMA在皮质的最佳水平。此外，我们表明，LIC2的高度保守的丝氨酸194磷酸化对于正确的纺锤体定向是必需的，它通过维持有丝分裂中心体的完整性来确保最佳的星体微管成核。这项工作揭示了LIC2-动力蛋白调节有丝分裂纺锤体定向的两种具体机制；即，通过一种新的相互作用蛋白转胶蛋白-2，它是LGN-NuMA与肌动蛋白皮质结合所必需的，以及通过LIC2的有丝分裂磷酸化来控制来自两极的微管成核。本文有对该论文第一作者的相关第一人称访谈。
