USP15 regulates TRIM21/GSDMD pathway to affect lipopolysaccharide-induced acute liver injury

Sepsis-induced liver injury is common in intensive care units and is associated with extremely low survival rates. Tripartite motif protein 21 (TRIM21) positively regulates Gasdermin D (GSDMD)-dependent pyroptosis via its PRY-SPRY domain; however, whether TRIM21 is involved in sepsis-induced liver injury is still unclear. In the present study, hepatic TRIM21 expression was dramatically upregulated in mice with LPS-induced liver injury. TRIM21 silencing in vivo alleviated pyroptosis and inflammation during sepsis-induced liver injury, as shown by a marked increase in GSDMD protein levels and a significant decrease in the protein levels of GSDMD N-terminal domain (GSDMD-N), IL-18 and IL-1β. A protein interaction screening revealed ubiquitin-specific peptidase 15 (USP15), a deubiquitinating enzyme, as a novel interactor of TRIM21. Notably, USP15 interacted with TRIM21 and maintained its stabilization through deubiquitination. In vivo, USP15 knockdown alleviated pyroptosis and inflammation in LPS-induced liver injury. Nevertheless, USP15 overexpression increased GSDMD-N, IL-18 and IL-1β protein expression and decreased GSDMD protein levels, and these effects were blocked by TRIM21 knockdown. In summary, TRIM21 induces GSDMD-N aggregation to increase pyroptosis and inflammation in LPS-induced liver injury, and USP15 serves as a critical regulator of TRIM21 by deubiquitinating and stabilizing the TRIM21 protein. Our results reveal the contribution of the USP15/TRIM21/GSDMD axis to cell pyroptosis in sepsis-induced liver injury, and this contribution could provide a novel approach for sepsis-induced liver injury treatment.