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In-vitro Reconstitution of Bacterial Ubiquitination and VCP/p97-mediated Elimination
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In-vitro Reconstitution of Bacterial Ubiquitination and VCP/p97-mediated Elimination

Published on: January 2, 2026

Integrated single-cell and bulk transcriptomic analyses reveal cDC1-centered ubiquitination dysregulation and

Cheng Li1, Yiman Han2, Zenglu Zheng2,3

  • 1Department of Anesthesiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Frontiers in Immunology
|May 8, 2026
PubMed
Abstract

Insights

Type-1 conventional dendritic cells (cDC1) drive immune dysregulation in sepsis via ubiquitination. Silencing UBE2F in cDC1s suppressed inflammation, reduced organ injury, and improved survival in septic mice, identifying UBE2F as a potential sepsis biomarker and therapeutic target.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genomics

Background:

  • Sepsis is a life-threatening condition characterized by immune dysregulation and organ dysfunction.
  • Current diagnostic biomarkers and therapeutic targets for sepsis remain insufficient.
  • The role of protein ubiquitination in sepsis-induced immune dysregulation and the specific immune cell subsets involved are not well-defined.

Purpose of the Study:

  • To identify specific immune cell subsets driving ubiquitination-associated immune dysregulation in human sepsis.
  • To investigate the potential of ubiquitination-related genes as diagnostic biomarkers and therapeutic targets for sepsis.

Main Methods:

  • Integrated analysis of single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic data from sepsis patients.
  • Cell-type responsiveness quantification using Augur and intercellular communication inference via CellChat.
  • Identification of ubiquitination-related gene networks using WGCNA and feature selection.
  • In vitro functional validation using LPS-stimulated dendritic cells (DCs) and in vivo validation using a cecal ligation and puncture (CLP) mouse model.

Main Results:

  • Conventional dendritic cells (cDCs), particularly the type-1 subset (cDC1), were identified as the most transcriptionally perturbed immune population in sepsis, showing activated ubiquitination signatures.
  • TNF signaling was identified as a sepsis-specific pathway mediated by cDC1 via the TNF-TNFRSF1B axis.
  • Four ubiquitination-related genes (CUL1, UBE2F, UBE2N, UBE3A) showed diagnostic potential, with UBE2F exhibiting the strongest upregulation and functional relevance.
  • Silencing UBE2F in vitro and in vivo suppressed DC activation, reduced pro-inflammatory cytokine production and organ injury, and improved survival in septic mice.

Conclusions:

  • Type-1 conventional dendritic cells (cDC1) are key immune players in sepsis-associated immune dysregulation through ubiquitination.
  • UBE2F demonstrates significant potential as a diagnostic biomarker and therapeutic target for sepsis.
Keywords:
UBE2Fdendritic cellssepsissingle-cell RNA sequencingubiquitination

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