https://ror.org/056swr059 Clinical Systems Biology Laboratories, Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Institute of Infection and Immunity, Henan Academy of Innovations in Medical Science, Zhengzhou, China.
Life Sci Alliance. 2024 Oct 28;8(1). doi: 10.26508/lsa.202402585. Print 2025 Jan.
Actin and microtubules are essential cytoskeletal components and coordinate their dynamics through multiple coupling and decoupling mechanisms. However, how actin and microtubule dynamics are decoupled remains incompletely understood. Here, we identified TBC1D3C as a new regulator that can decouple actin filament assembly from microtubule disassembly. We showed that TBC1D3C induces the release of GEF-H1 from microtubules into the cytosol without perturbing microtubule arrays, leading to RhoA activation and actin filament assembly. Mechanistically, we found that TBC1D3C directly binds to GEF-H1, disrupting its interaction with the Tctex-DIC-14-3-3 complex and thereby displacing GEF-H1 from microtubules independently of microtubule disassembly. Super-resolution microscopy and live-cell imaging further confirmed that TBC1D3C triggers GEF-H1 release and actin filament assembly while maintaining microtubule integrity. Therefore, our findings demonstrated that TBC1D3C functions as a direct GEF activator and a novel regulator in decoupling actin assembly from microtubule disassembly, providing new insights into cytoskeletal regulation.
肌动蛋白和微管是细胞骨架的基本组成部分，通过多种偶联和解偶联机制来协调它们的动力学。然而，肌动蛋白和微管动力学如何解偶联仍不完全清楚。在这里，我们鉴定出 TBC1D3C 是一种新的调节剂，可将肌动蛋白丝组装与微管解聚解偶联。我们表明，TBC1D3C 可诱导 GEF-H1 从微管释放到细胞质中，而不会扰乱微管排列，从而导致 RhoA 激活和肌动蛋白丝组装。在机制上，我们发现 TBC1D3C 直接与 GEF-H1 结合，破坏其与 Tctex-DIC-14-3-3 复合物的相互作用，从而将 GEF-H1 从微管上置换出来，而无需微管解聚。超分辨率显微镜和活细胞成像进一步证实，TBC1D3C 触发 GEF-H1 释放和肌动蛋白丝组装，同时保持微管完整性。因此，我们的研究结果表明，TBC1D3C 作为一种直接的 GEF 激活剂和将肌动蛋白组装与微管解聚解偶联的新调节剂，为细胞骨架调节提供了新的见解。
