Tripartite motif 13 orchestrates endoplasmic reticulum-associated degradation and endoplasmic reticulum-phagy to modulate dendritic cell-mediated immune responses in sepsis

Sepsis is a life-threatening condition characterized by profound immune dysregulation and organ dysfunction. The functional impairment of dendritic cells (DCs) in septic patients is well-documented and contributes significantly to sepsis-induced immunosuppression; yet the underlying mechanisms remain poorly understood. Tripartite motif 13 (TRIM13) has been identified as an immune regulator with predominantly suppressive effects. Here, we aimed to investigate the potential role of TRIM13 restriction in promoting the DC-mediated immune response during sepsis.

Splenic DCs were isolated from wild-type (WT) and DC-specific Trim13 conditional knockout (Trim13 cKO) mice post-cecum ligation and puncture (CLP). These cells were subsequently analyzed by proteomics, immunoblotting, flow cytometry, and transmission electron microscopy (TEM). DC2.4 cells were infected with either Trim13 shRNA or a Trim13 overexpression lentiviral vector and treated with different pharmacological inhibitors. Protein interactions were examined via coimmunoprecipitation (Co-IP) and confocal microscopy. Cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA), and organ lesions were assessed through hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC) for CD45, and TUNEL assays.

TRIM13 expression was rapidly upregulated in DCs following septic challenge. Deletion of TRIM13 in DCs disrupted the endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-selective autophagy (ER-phagy)-mediated degradation of the stimulator of interferon genes (STING), leading to sustained STING activation and enhanced DC function. STING signaling promoted the p-IRF3 nuclear translocation, NLRP3 inflammasome priming, and transient DC pyroptosis, thereby exacerbating hyperinflammation in the acute phase of sepsis. Over the longer term, prolonged STING signaling inhibited DCs from adopting the immunosuppressive phenotype and promoting the DC-mediated immune response. Ultimately, TRIM13 deficiency in DCs ameliorated sepsis-induced immunosuppression, preserved organ function in the late phase of sepsis, and reduced overall mortality in septic mice.

TRIM13 acts as a key negative regulator of DC function during sepsis. Restricting TRIM13 sustains DC immunostimulatory property, counteracts sepsis-induced immunosuppression, and improves survival outcomes. These findings highlight TRIM13 as a potential therapeutic target for sepsis management.