Smith Claire E L, Lake Alice V R, Johnson Colin A
Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom.
Front Cell Dev Biol. 2020 Dec 17;8:622822. doi: 10.3389/fcell.2020.622822. eCollection 2020.
Primary cilia are microtubule-based organelles that extend from the apical surface of most mammalian cells, forming when the basal body (derived from the mother centriole) docks at the apical cell membrane. They act as universal cellular "antennae" in vertebrates that receive and integrate mechanical and chemical signals from the extracellular environment, serving diverse roles in chemo-, mechano- and photo-sensation that control developmental signaling, cell polarity and cell proliferation. Mutations in ciliary genes cause a major group of inherited developmental disorders called ciliopathies. There are very few preventative treatments or new therapeutic interventions that modify disease progression or the long-term outlook of patients with these conditions. Recent work has identified at least four distinct but interrelated cellular processes that regulate cilia formation and maintenance, comprising the cell cycle, cellular proteostasis, signaling pathways and structural influences of the actin cytoskeleton. The actin cytoskeleton is composed of microfilaments that are formed from filamentous (F) polymers of globular G-actin subunits. Actin filaments are organized into bundles and networks, and are attached to the cell membrane, by diverse cross-linking proteins. During cell migration, actin filament bundles form either radially at the leading edge or as axial stress fibers. Early studies demonstrated that loss-of-function mutations in ciliopathy genes increased stress fiber formation and impaired ciliogenesis whereas pharmacological inhibition of actin polymerization promoted ciliogenesis. These studies suggest that polymerization of the actin cytoskeleton, F-actin branching and the formation of stress fibers all inhibit primary cilium formation, whereas depolymerization or depletion of actin enhance ciliogenesis. Here, we review the mechanistic basis for these effects on ciliogenesis, which comprise several cellular processes acting in concert at different timescales. Actin polymerization is both a physical barrier to both cilia-targeted vesicle transport and to the membrane remodeling required for ciliogenesis. In contrast, actin may cause cilia loss by localizing disassembly factors at the ciliary base, and F-actin branching may itself activate the YAP/TAZ pathway to promote cilia disassembly. The fundamental role of actin polymerization in the control of ciliogenesis may present potential new targets for disease-modifying therapeutic approaches in treating ciliopathies.
初级纤毛是基于微管的细胞器，从大多数哺乳动物细胞的顶端表面伸出，当基体（源自母中心粒）对接在顶端细胞膜时形成。在脊椎动物中，它们充当通用的细胞“天线”，接收并整合来自细胞外环境的机械和化学信号，在化学、机械和光感知中发挥多种作用，控制发育信号传导、细胞极性和细胞增殖。纤毛基因的突变会导致一大类遗传性发育障碍，称为纤毛病。几乎没有预防性治疗方法或新的治疗干预措施可以改变疾病进展或改善这些疾病患者的长期预后。最近的研究确定了至少四个不同但相互关联的细胞过程来调节纤毛的形成和维持，包括细胞周期、细胞蛋白质稳态、信号通路以及肌动蛋白细胞骨架的结构影响。肌动蛋白细胞骨架由微丝组成，微丝由球状G-肌动蛋白亚基的丝状（F）聚合物形成。肌动蛋白丝被组织成束和网络，并通过多种交联蛋白附着在细胞膜上。在细胞迁移过程中，肌动蛋白丝束要么在前缘呈放射状形成，要么形成轴向应力纤维。早期研究表明，纤毛病基因的功能丧失突变会增加应力纤维的形成并损害纤毛发生，而肌动蛋白聚合的药理学抑制则促进纤毛发生。这些研究表明，肌动蛋白细胞骨架的聚合、F-肌动蛋白分支和应力纤维的形成均抑制初级纤毛的形成，而肌动蛋白的解聚或消耗则增强纤毛发生。在这里，我们综述了这些对纤毛发生影响的机制基础，这些机制包括在不同时间尺度上协同作用的几个细胞过程。肌动蛋白聚合既是针对纤毛的囊泡运输的物理障碍，也是纤毛发生所需的膜重塑的物理障碍。相比之下，肌动蛋白可能通过在纤毛基部定位拆卸因子来导致纤毛丢失，并且F-肌动蛋白分支本身可能激活YAP/TAZ途径以促进纤毛拆卸。肌动蛋白聚合在控制纤毛发生中的基本作用可能为治疗纤毛病的疾病修饰治疗方法提供潜在的新靶点。
