A bacterial genotoxin reveals a p53-proteasome-LC3 regulatory axis that drives the suppression of autophagy in cells experiencing sublethal DNA damage

D'Feau J Lieu; Molly K Crowder; Jordan R Kryza; Batcha Tamilselvam; Paul J Kaminski; Ik-Jung Kim; Ying-Xing Li; Eunji Jeong; Michidmaa Enkhbaatar; Henry Chen; Sophia B Son; Hanlin Mok; Kenneth A Bradley; Heidi Phillips; Steven R Blanke

doi:10.1016/j.isci.2025.112118

A bacterial genotoxin reveals a p53-proteasome-LC3 regulatory axis that drives the suppression of autophagy in cells experiencing sublethal DNA damage

iScience. 2025 Feb 27;28(4):112118. doi: 10.1016/j.isci.2025.112118. eCollection 2025 Apr 18.

Authors

D'Feau J Lieu¹, Molly K Crowder¹, Jordan R Kryza¹, Batcha Tamilselvam¹, Paul J Kaminski¹, Ik-Jung Kim¹, Ying-Xing Li¹, Eunji Jeong¹, Michidmaa Enkhbaatar¹, Henry Chen¹, Sophia B Son¹, Hanlin Mok¹, Kenneth A Bradley², Heidi Phillips³, Steven R Blanke^{1

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Affiliations

¹ Department of Microbiology, University of Illinois, Urbana, IL 61801, USA.
² Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802, USA.
⁴ Department of Pathobiology, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802, USA.
⁵ Biomedical and Translational Sciences Department, Carle-Illinois College of Medicine, Urbana, IL 61801, USA.

Abstract

Macroautophagy is thought to have a critical role in shaping and refining cellular proteostasis in eukaryotic cells recovering from DNA damage. Autophagy activation has been previously reported in DNA-damaged cells, often in association with increased cellular cytotoxicity. However, we now report a mechanism by which autophagy is suppressed in the absence of cytotoxicity within cells exposed to bacterial toxin-, chemical-, or radiation-mediated sources of genotoxicity. Specifically, our studies demonstrate the DNA damage response-dependent stabilization of the tumor suppressor p53, which is both required and sufficient for regulating the ubiquitination and proteasome-dependent reduction in cellular pools of microtubule-associated protein 1 light chain 3 (LC3A/B), a key precursor of autophagosome biogenesis and maturation, in both epithelial cells and an ex vivo organoid model. Our data indicate that the suppression of autophagy, through a p53-proteasome-LC3 regulatory axis, is a conserved cellular response to multiple sources of genotoxicity. Such a mechanism could provide a means for realigning proteostasis in cells undergoing DNA damage repair.

Keywords: biological sciences; cell biology; molecular biology.