TP53/TAU axis regulates microtubule bundling to control alveolar stem cell-mediated regeneration

Cells exhibit diverse sizes and shapes, tailored for functional needs of tissues. Lung alveoli are lined by large, extremely thin epithelial alveolar type 1 cells (AT1s). Their characteristic morphology is essential for lung function and must be restored after injury. The mechanisms underlying small, cuboidal alveolar type 2 cell (AT2) differentiation into thin AT1s remain elusive. Here, we demonstrated that AT2s undergo a stepwise morphological transformation characterized by the development of a unique thick microtubule (MT) bundle organization, critical for AT1 morphology. Using AT2 cultures and in vivo genetic loss-of-function models, we found that MT bundling occurred in a transitional cell state during AT2 differentiation and was regulated by the TP53/TAU (encoded by the microtubule-associated protein tau [MAPT] gene) signaling axis. Notably, TAU underwent a linear clustering process, forming beads-on-a-string-like pattern that preceded thick MT bundle formation. Genetic gain or loss of function of TAU in mouse or human models prevented the formation of thick MT bundles, highlighting the critical role of precise TAU levels in generating ultrathin AT1s. This defect was associated with increased tissue fibrosis following bleomycin-induced injury in vivo. GWAS analysis revealed risk variants in the MAPT locus in lung diseases. Moreover, TP53 controlled TAU expression and its loss phenocopied TAU deficiency. This work revealed an unexpected role for TAU in organizing MT bundles during AT2 differentiation.