State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2158-63. doi: 10.1073/pnas.1319341111. Epub 2014 Jan 27.
Oriented cell division is critical for cell fate specification, tissue organization, and tissue homeostasis, and relies on proper orientation of the mitotic spindle. The molecular mechanisms underlying the regulation of spindle orientation remain largely unknown. Herein, we identify a critical role for cylindromatosis (CYLD), a deubiquitinase and regulator of microtubule dynamics, in the control of spindle orientation. CYLD is highly expressed in mitosis and promotes spindle orientation by stabilizing astral microtubules and deubiquitinating the cortical polarity protein dishevelled. The deubiquitination of dishevelled enhances its interaction with nuclear mitotic apparatus, stimulating the cortical localization of nuclear mitotic apparatus and the dynein/dynactin motor complex, a requirement for generating pulling forces on astral microtubules. These findings uncover CYLD as an important player in the orientation of the mitotic spindle and cell division and have important implications in health and disease.
定向细胞分裂对于细胞命运特化、组织组织和组织稳态至关重要，并且依赖于有丝分裂纺锤体的正确定向。调节纺锤体定向的分子机制在很大程度上仍然未知。本文中，我们发现了一个关键角色——Cylindromatosis（CYLD），一种去泛素化酶和微管动力学调节剂，在控制纺锤体定向中的作用。CYLD 在有丝分裂中高度表达，并通过稳定星状微管和去泛素化皮质极性蛋白 Dishevelled 来促进纺锤体定向。Dishevelled 的去泛素化增强了其与核有丝分裂装置的相互作用，刺激核有丝分裂装置和动力蛋白/动力蛋白复合物的皮质定位，这是对星状微管产生拉力的要求。这些发现揭示了 CYLD 作为有丝分裂纺锤体和细胞分裂定向的重要参与者，并在健康和疾病方面具有重要意义。
