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ResearchIn-Press PreviewCell biologyPulmonology Open Access | 10.1172/JCI194762

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

Satoshi Konishi,1 Khaliun Enkhbayar,2 Shuyu Liu,1 Naoya Miyashita,1 Yoshihiko Kobayashi,2 Vera Hutchison,3 Ashna Sai,1 Pankaj Agarwal,2 Jonathan Witonsky,4 Nathan D. Jackson,5 Max A. Seibold,5 Jichao Chen,3 Aleksandra Tata,1 and Purushothama Rao Tata2

1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

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1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

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1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

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1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

Find articles by Miyashita, N. in: PubMed | Google Scholar

1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

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1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

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1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

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1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

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1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

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1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

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1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

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1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

Find articles by Chen, J. in: PubMed | Google Scholar

1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

Find articles by Tata, A. in: PubMed | Google Scholar

1Department of Cell Biology, Duke Univeristy School of Medicine, Durham, United States of America

2Department of Cell Biology, Duke University School of Medicine, Durham, United States of America

3Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States of America

4Department of Pediatrics, UCSF, San Francisco, United States of America

5Center for Genes Environment and Health, National Jewish Health, Denver, United States of America

Find articles by Tata, P. in: PubMed | Google Scholar

Published February 5, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI194762.
Copyright © 2026, Konishi et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 5, 2026 - Version history
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Abstract

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 cells (AT2s) 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 process occurs in a transitional cell state during AT2 differentiation and was regulated by the TP53/TAU 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 ultra-thin AT1s. This defect was associated with increased tissue fibrosis following bleomycin-induced injury in vivo. GWAS analysis revealed risk variants in 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.

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  • Version 1 (February 5, 2026): In-Press Preview
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