2025年12月8日出版的《细胞》杂志发表了瑞士科学家的一项最新研究成果。来自PSI生命科学中心的Michel O. Steinmetz小组研究出微管介导信号转导的结构基础。
研究人员确定了微管调节鸟嘌呤核苷酸交换因子H1 （GEFH1）的结构基础，该因子是Ras同源家族成员a （RhoA）途径的关键激活因子。研究小组发现微管晶格的特定特征与GEFH1的C1结构域结合，导致该信号蛋白的隔离和失活。C1残基的靶向突变破坏了这种相互作用，触发GEFH1释放和RhoA依赖性免疫反应的激活。基于这种隔离和释放机制，研究人员在其他信号蛋白中发现了微管结合C1结构域，包括其他鸟嘌呤核苷酸交换因子（GEFs）、激酶、GTPase激活蛋白（GAP）和肿瘤抑制因子，并表明微管通过C1结构域介导的调节在含有Ras关联结构域的蛋白1A （RASSF1A）中是保守的。他们的发现为理解微管如何作为时空信号传感器，整合和处理不同的信号通路来控制重要的细胞过程建立了一个结构框架。
据了解，微管一直被认为是细胞内信号传导的上游介质，但其基本功能的机制仍不清楚。
附：英文原文
Title: Structural basis of microtubule-mediated signal transduction
Author: Sung Ryul Choi, Thorsten B. Blum, Matteo Giono, Bibhas Roy, Ioannis Vakonakis, Dominic Schmid, Nicole Oelgarth, Apisha Ranganathan, Alvar D. Gossert, G.V. Shivashankar, Alfred Zippelius, Michel O. Steinmetz
Issue&Volume: 2025-12-08
Abstract: Microtubules have long been recognized as upstream mediators of intracellular signaling, but the mechanisms underlying this fundamental function remain elusive. Here, we identify the structural basis by which microtubules regulate the guanine nucleotide exchange factor H1 (GEFH1), a key activator of the Ras homolog family member A (RhoA) pathway. We show that specific features of the microtubule lattice bind the C1 domain of GEFH1, leading to the sequestration and inactivation of this signaling protein. Targeted mutations in C1 residues disrupt this interaction, triggering GEFH1 release and activation of RhoA-dependent immune responses. Building on this sequestration-and-release mechanism, we identify microtubule-binding C1 domains in additional signaling proteins, including other guanine nucleotide exchange factors (GEFs), kinases, a GTPase-activating protein (GAP), and a tumor suppressor, and show that microtubule-mediated regulation via C1 domains is conserved in the Ras association domain-containing protein 1A (RASSF1A). Our findings establish a structural framework for understanding how microtubules can function as spatiotemporal signal sensors, integrating and processing diverse signaling pathways to control important cellular processes.
DOI: 10.1016/j.cell.2025.11.011
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01307-8