Proteasome-dependent cytoskeleton disruption during Leptospira interrogans infection induces aberrant collective cell migration.

Authors

Hunter Barbee, Isabel Sebastián, Romina Tokumon, Yaru Wang, Tetsu Yamashiro, Claudia Toma

Published in

PLoS pathogens. Volume 22. Issue 8. Pages e1014501. Aug 07, 2026. Epub Aug 07, 2026.

Abstract

Leptospira interrogans is a causative agent of leptospirosis, a potentially life-threatening zoonotic disease. A major symptom of severe leptospirosis is acute kidney failure; this is characterized by the detachment of renal proximal tubule epithelial cells (RPTECs) from the basement membrane, which can lead to chronic kidney disease. The kidneys possess an intrinsic ability to self-repair following acute injury through collective cell migration; this process involves the movement of cells as cohesive units. Mechanical forces transmitted between cells via mechanosensors are important for this migration process. L. interrogans induces the displacement of mechanosensors from the plasma membrane, which can be prevented by inhibitors of eukaryotic proteolytic pathways. However, the effects of mechanosensors dysfunction on epithelial repair processes have not been investigated yet. Therefore, the aim of this study was to analyze proteasomal inhibition during epithelial barrier disruption and elucidate epithelial repair mechanisms by examining collective migration of infected RPTECs. We performed a proteome-wide analysis of protein ubiquitination in infected-RPTECs to understand the effect of proteasomal inhibitors. Moreover, we detected increased ubiquitination of ADP-ribosylation factor-like protein 2 (ARL2), a protein involved in microtubule dynamics. Immunofluorescence analysis revealed that L. interrogans induces proteasome-dependent disruption of the microtubule and F-actin cytoskeletal network. Scratch assays revealed aberrant collective cell migration and delayed wound healing in L. interrogans-infected RPTECs. Wound healing was improved by proteasomal inhibition followed by the addition of epidermal growth factor. In conclusion, our findings suggest that L. interrogans alters the circuit integrating mechanosensors at cell-cell contact junctions and the supracellular F-actin and microtubule cytoskeletal network, thereby disrupting epithelial repair responses.

PMID:
42566480
Bibliographic data and abstract were imported from PubMed on 08 Aug 2026.

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