Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland.
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
Nat Commun. 2024 Nov 17;15(1):9963. doi: 10.1038/s41467-024-54036-0.
Microtubules, built from heterodimers of α- and β-tubulins, control cell shape, mediate intracellular transport, and power cell division. The concentration of αβ-tubulins is tightly controlled through a posttranscriptional mechanism involving selective and regulated degradation of tubulin-encoding mRNAs. Degradation is initiated by TTC5, which recognizes tubulin-synthesizing ribosomes and recruits downstream effectors to trigger mRNA deadenylation. Here, we investigate how cells regulate TTC5 activity. Biochemical and structural proteomic approaches reveal that under normal conditions, soluble αβ-tubulins bind to and sequester TTC5, preventing it from engaging nascent tubulins at translating ribosomes. We identify the flexible C-terminal tail of TTC5 as a molecular switch, toggling between soluble αβ-tubulin-bound and nascent tubulin-bound states. Loss of sequestration by soluble αβ-tubulins constitutively activates TTC5, leading to diminished tubulin mRNA levels and compromised microtubule-dependent chromosome segregation during cell division. Our findings provide a paradigm for how cells regulate the activity of a specificity factor to adapt posttranscriptional regulation of gene expression to cellular needs.
微管由α-和β-微管蛋白组成的异二聚体构成，控制着细胞的形状，介导细胞内运输，并为细胞分裂提供动力。αβ-微管蛋白的浓度通过涉及微管蛋白编码 mRNA 的选择性和调节性降解的转录后机制来严格控制。降解由 TTC5 启动，TTC5 识别合成微管的核糖体，并招募下游效应物来触发 mRNA 的去腺苷酸化。在这里，我们研究细胞如何调节 TTC5 的活性。生化和结构蛋白质组学方法揭示，在正常情况下，可溶性的 αβ-微管蛋白与 TTC5 结合并将其隔离，从而防止其与翻译核糖体上的新生微管结合。我们确定 TTC5 的柔性 C 末端尾巴为分子开关，在可溶性 αβ-微管蛋白结合状态和新生微管结合状态之间切换。可溶性 αβ-微管蛋白失去隔离作用会使 TTC5 持续激活，导致微管蛋白 mRNA 水平降低，并在细胞分裂期间损害微管依赖性染色体分离。我们的研究结果为细胞如何调节特异性因子的活性以适应基因表达的转录后调控以满足细胞需求提供了范例。
