Septin 9 PB domains coordinate centrosome positioning and microtubule acetylation to control epithelial polarity

Septins are cytoskeletal GTP-binding proteins that organize microtubules and scaffold polarity complexes. Here, we uncover a polybasic (PB)-domain-dependent mechanism by which septin 9 controls apico-basal polarity in epithelial cells. Septin 9 regulates centrosome positioning and the asymmetric distribution of acetylated microtubules, which are required for ciliogenesis and lumen formation. Knockdown of septin 9 or deletion of its PB domains disrupts centrosome asymmetry, induces a symmetric distribution of acetylated tubulin, and impairs cilia formation, leading to polarity inversion. These defects are associated with increased expression of the microtubule deacetylase HDAC6. Importantly, inhibition of TGF-β signaling or selective HDAC6 inhibition with tubacin restores microtubule acetylation and rescues apico-basal polarity. Together, our findings identify septin 9 as a cytoskeletal integrator that links centrosome positioning and microtubule acetylation to epithelial morphogenesis through the TGF-β/HDAC6 pathway.