Tubulin autoregulation tunes microtubule dynamics
to support multicellular architecture

Ana Almeida

Alpha- and beta-tubulin heterodimers dynamically assemble into microtubules, key cytoskeletal elements involved in intracellular trafficking, cell adhesion and division. The availability of free tubulins regulates the synthesis of new subunits. In response to excessive soluble αβ-tubulins, tetratricopeptide protein 5 (TTC5) selectively recognizes nascent tubulins at the ribosome, recruiting downstream effectors that degrade their encoding messenger RNAs, in a process known as tubulin autoregulation. Despite its well-characterized molecular framework, the biological relevance of this regulatory pathway remains unknown. Here, using 3D cellular models, advanced optics, and genetic perturbation of tubulin biosynthesis, we reveal that loss of TTC5-dependent tubulin autoregulation elevates soluble tubulin levels, inducing microtubule hyperstability, and disrupting cytoskeletal organization. These defects impair the localization of adhesion molecules at cell-cell junctions and extracellular matrix interfaces, compromising tissue architecture and reducing overall cell viability. Our findings establish tubulin autoregulation as a critical mechanism that tunes microtubule dynamics to sustain cellular integrity and tissue homeostasis.