USP10: A Promising Catalyst for Combating Sepsis-Induced Intestinal Injury via PLK1 Deubiquitination and Stabilization

Abstract

Background: Ubiquitin-specific peptidase 10 (USP10), a deubiquitinating enzyme, enhances the stability of substrate protein through deubiquitination. While earlier studies have shown that USP10 mitigates kidney damage in sepsis, its role in sepsis-induced intestinal injury remains unclear. Methods: A septic intestinal injury model was created in vivo using cecal ligation and puncture (CLP), while an in vitro model was established by treating IEC-6 intestinal epithelial cells with lipopolysaccharide (LPS). Histopathological changes in intestinal tissues were examined using hematoxylin-eosin staining. Interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) levels in intestinal tissues were measured using enzyme linked immunosorbent assay (ELISA) assay. TdT-mediated dUTP nick end labeling (TUNEL) assay was used to assess intestinal tissue cells apoptosis, and flow cytometry was employed to determine the apoptosis rate in IEC-6 cells. USP10 impact on Polo-like kinase 1 (PLK1) expression was analyzed using Western blot assay, while immunoprecipitation was employed to detect interactions between USP10 and PLK1. Ubiquitination levels of PLK1 were determined to evaluate USP10s influence, and rescue experiments were conducted to verify whether USP10 alleviates septic intestinal injury by regulating PLK1. Results: Treatment with either CLP or LPS increased IL-6, IL-1β, TNF-α, and apoptosis rates in intestinal tissues or cells. However, USP10 overexpression reduced the levels of inflammatory factor and suppressed apoptosis. Mechanistically, USP10 interacted with and positively regulated PLK1 while decreasing its ubiquitination levels. Rescue experiment results demonstrated that the protective effect of USP10 on the septic intestinal injury was reversed by siRNA-PLK1. Conclusions: USP10 mitigates septic intestinal injury by stabilizing PLK1 via deubiquitination, reducing inflammation and apoptosis. This finding implies that USP10 might be a promising therapeutic target for managing septic bowel damage.