Tubulin autoregulation controls the biosynthesis of γ-tubulin to ensure mitotic fidelity

Abstract Microtubule organization relies on the precise control of tubulin abundance to ensure accurate cytoskeletal function and faithful cell division. While α- and β-tubulin levels are controlled by a well-characterized autoregulatory pathway that triggers co-translational mRNA decay in response to excess soluble tubulin, how cells regulate the abundance of the core microtubule nucleator γ-tubulin has remained unclear. Here, we show that γ-tubulin is regulated by the canonical tubulin autoregulatory machinery. We find that γ-tubulin-encoding mRNAs are downregulated in response to elevated soluble αβ-tubulin levels. This regulation requires TTC5 to co-translationally recognize a conserved amino-terminal MPREI motif in nascent γ-tubulin proteins, and further recruit SCAPER and CCR4-NOT complex, targeting γ-tubulin mRNAs for decay. Disruption of this regulatory mechanism elevates γ-tubulin protein levels, increases centrosomal microtubule nucleation output, and compromises mitotic fidelity. Together, our findings establish γ-tubulin as a previously unrecognized substrate of tubulin autoregulation and reveal coordinated control of tubulin biosynthesis as a key mechanism for tuning microtubule nucleation and ensuring accurate chromosome segregation.