Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King's College London, SE1 1UL London, United Kingdom.
School of Cancer and Pharmaceutical Sciences, King's College London, SE1 1UL London, United Kingdom.
Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2138-2143. doi: 10.1073/pnas.1722281115. Epub 2018 Feb 8.
During cytokinesis, a cleavage furrow generated by actomyosin ring contraction is restructured into the midbody, a platform for the assembly of the abscission machinery that controls the final separation of daughter cells. The polymerization state of F-actin is important during assembly, ingression, disassembly, and closure of the contractile ring and for the cytoskeletal remodeling that accompanies midbody formation and progression to abscission. Actin filaments must be cleared from the abscission sites before the final cut can take place. Although many conserved proteins interact with and influence the polymerization state of actin filaments, it is poorly understood how they regulate cytokinesis in higher eukaryotes. We report here that the actin capping protein (CP), a barbed end actin binding protein, participates in the control of actin polymerization during later stages of cytokinesis in human cells. Cells depleted of CP furrow and form early midbodies, but they fail cytokinesis. Appropriate recruitment of the ESCRT-III abscission machinery to the midbody is impaired, preventing the cell from progressing to the abscission stage. To generate actin filaments of optimal length, different actin nucleators, such as formins, balance CP's activity. Loss of actin capping activity leads to excessive accumulation of formin-based linear actin filaments. Depletion of the formin FHOD1 results in partial rescue of CP-induced cytokinesis failure, suggesting that it can antagonize CP activity during midbody maturation. Our work suggests that the actin cytoskeleton is remodeled in a stepwise manner during cytokinesis, with different regulators at different stages required for successful progression to abscission.
在胞质分裂过程中，由肌动球蛋白环收缩产生的分裂沟被重构为中体，这是装配分离机器的平台，该机器控制子细胞的最终分离。在收缩环的装配、内陷、解体和闭合以及伴随中体形成和向分离进展的细胞骨架重排过程中，F-肌动蛋白的聚合状态很重要。在最终切割之前，必须从分离部位清除肌动蛋白丝。尽管许多保守蛋白与肌动蛋白丝的聚合状态相互作用并影响其聚合状态，但人们对它们如何在高等真核生物中调节胞质分裂知之甚少。我们在此报告，肌动蛋白加帽蛋白（CP），一种带帽的肌动蛋白结合蛋白，参与人类细胞胞质分裂后期肌动蛋白聚合的控制。CP 耗尽的细胞出现沟和早期中体，但它们不能进行胞质分裂。ESCRT-III 分离机器适当募集到中体受到损害，阻止细胞进入分离阶段。为了生成最佳长度的肌动蛋白丝，不同的肌动蛋白成核因子，如formin，平衡 CP 的活性。肌动蛋白加帽活性的丧失导致基于formin 的线性肌动蛋白丝的过度积累。formin FHOD1 的耗尽导致 CP 诱导的胞质分裂失败的部分挽救，表明它可以在中体成熟过程中拮抗 CP 活性。我们的工作表明，在胞质分裂过程中，肌动蛋白细胞骨架以逐步的方式重塑，在成功进展到分离阶段需要不同的调节剂在不同的阶段。
