UBE2F Identified as Key Regulator of Ubiquitination Dysregulation in cDC1 During Sepsis

Overview

This study reveals that type-1 conventional dendritic cells (cDC1) exhibit pronounced ubiquitination dysregulation in sepsis, mediated via the TNF–TNFRSF1B axis. UBE2F, among four key ubiquitination-related genes, shows strong upregulation and functional relevance, with silencing improving outcomes in septic mouse models.

Background

Sepsis is a life-threatening syndrome characterized by dysregulated immune responses and multiple organ dysfunction, with high mortality despite advances in care. Protein ubiquitination plays a critical role in regulating inflammation and immune cell function, but the specific immune cell subsets driving ubiquitination-associated dysregulation in sepsis remain unclear. Single-cell and bulk transcriptomic analyses offer powerful tools to dissect cellular heterogeneity and identify molecular regulators in sepsis.

Data Highlights

Key Findings

• cDC1 subset is the most transcriptionally perturbed immune cell population in sepsis with activated ubiquitination signatures.
• TNF signaling via the TNF–TNFRSF1B axis is a sepsis-specific pathway with cDC1 as a critical mediator.
• Four ubiquitination-related genes (CUL1, UBE2F, UBE2N, UBE3A) show reproducible diagnostic performance across independent cohorts.
• UBE2F is the most strongly upregulated gene and functionally relevant in sepsis models.
• Silencing UBE2F in vitro and in vivo reduces dendritic cell activation, proinflammatory cytokine production, organ injury, and improves survival in septic mice.

Clinical Implications

UBE2F represents a promising diagnostic biomarker and therapeutic target for sepsis, particularly by modulating cDC1-mediated immune dysregulation. Targeting ubiquitination pathways in cDC1 may offer novel strategies to attenuate inflammation and organ damage in sepsis, potentially improving patient outcomes.

Conclusion

This integrative transcriptomic analysis identifies cDC1 and UBE2F as central players in ubiquitination-mediated immune dysregulation during sepsis, providing a mechanistic basis for precision diagnostics and targeted therapies.

References

1. Comprehensive Transcriptomic Analysis of Single Cells and Bulk Samples Uncovers UBE2F as a Key Regulator of Ubiquitination Dysregulation in cDC1 During Sepsis