Autoregulation of tubulin mRNA via reversible TTC5 sequestration by soluble αβ-tubulins

The microtubule cytoskeleton, built from heterodimers of α and β-tubulins, is critically important to physically organize cells, mediate intracellular transport and power cell division. The availability of soluble αβ-tubulins influences the biomechanical properties and dynamic functions of microtubules. When present in excess, soluble αβ-tubulins induce degradation of their encoding mRNAs. This process involves the specificity factor TTC5, which recognizes nascent tubulins and recruits effectors that degrade the mRNA. But how TTC5 activity is regulated is unknown. Our biochemical and structural proteomic approaches reveal that soluble αβ-tubulins sequester TTC5 at steady-state, repressing its activity. The carboxy-terminal domain of TTC5 acts as a molecular switch, toggling between soluble αβ-tubulin-bound and nascent tubulin-bound states. Loss-of-function mutantions that abolish sequestration by soluble αβ-tubulins constitutively activate 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.