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TRIM11 modulates sepsis progression by promoting HOXB9 ubiquitination and inducing the NF-κB signaling pathway

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Abstract

Introduction

The purpose of this investigation was to elucidate the functions of TRIM11 and HOXB9 in the pathogenesis of sepsis, focusing on their influence on inflammation, apoptosis, and the NF-κB signaling pathway.

Material and methods

Through public databases, TRIM family genes related to sepsis were screened, and TRIM11 was evaluated as a sepsis biomarker through ROC analysis. The UbiBrowser database screened TRIM11 downstream genes and identified HOXB9 as an essential target. THP-1 cells were stimulated by Lipopolysaccharide (LPS) to induce inflammation and simulate sepsis. Flow cytometry, Enzyme-linked immunosorbent assay, and Western blot experiments were used to detect changes in cell apoptosis rate, apoptosis-related proteins, and inflammatory cytokines after TRIM11 and HOXB9 were silenced. Additionally, we investigated the ubiquitination interaction between TRIM11 and HOXB9 and their effects on the NF-κB signaling pathway.

Results

Our findings demonstrated that sepsis patient samples had elevated levels of TRIM11 expression and had high clinical diagnostic value. Functional experiments showed that the knockdown of TRIM11 significantly alleviated LPS-induced THP-1 cell apoptosis and inflammation, while the knockdown of HOXB9 did the opposite. The simultaneous downregulation of TRIM11 and HOXB9 balanced these responses, suggesting they play a key role in regulating sepsis-associated inflammation and apoptosis. In addition, TRIM11 regulated the NF-κB signaling pathway by reversing HOXB9-induced activation through ubiquitination, suggesting a novel regulatory mechanism in the pathogenesis of sepsis.

Conclusions

Our findings highlight the interaction between TRIM11 and HOXB9 in regulating inflammation and apoptosis pathways, providing new insights into sepsis treatment.

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Data availability

No datasets were generated or analysed during the current study.

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Author notes

  1. Jiaqi Gan and Wei Zhang have contributed equally to this work.

Authors and Affiliations

  1. Department of General Medicine, Minhang Hospital, Fudan University, 170 Xinsong Road, Shanghai, 201199, China

    Jiaqi Gan & Fei Pan

  2. The First People’s Hospital of Lianyungang Graduate Student Training Base, Jinzhou Medical University, No.6 East Zhenhua Road, Lianyungang, 222061, China

    Xiaobing Chen

  3. Emergency Medical Department, Minhang Hospital, Fudan University, 170 Xinsong Road, Shanghai, 201199, China

    Wei Zhang & Zhiyun Qiu

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Contributions

Conception and design of the research: Jiaqi Gan, Fei Pan Acquisition of data: Jiaqi Gan, Fei Pan, Wei Zhang Analysis and interpretation of data: Xiaobing Chen, Zhiyun Qiu Statistical analysis: Jiaqi Gan, Wei Zhang, Zhiyun Qiu Drafting the manuscript: Wei Zhang, Zhiyun Qiu, Jiaqi Gan Revision of manuscript for important intellectual content: Fei Pan, Jiaqi Gan.

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Correspondence to Zhiyun Qiu or Xiaobing Chen.

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Supplementary file1 (ZIP 67915 KB)

11033_2024_10212_MOESM2_ESM.tif

Supplementary file2 (TIF 11999 KB)—Supplementary Figure 1. Modular analysis and diagnostic efficacy of TRIM family genes in the GSE13205 and GSE46955 datasets. (A) Sample dendrogram and trait heat map, different branches represent different GSE13205 dataset samples. (B) Gene dendrogram obtained by average linkage hierarchical clustering. The colored rows below the dendrogram show module assignments determined by dynamic tree cuts. (C) Eigengene adjacency heat map of the correlation between module eigengenes and sample traits. (D and E) Enrichment analysis of 1098 genes in the turquoise module. The x-axis represents the gene ratio; the y-axis represents the GO term or enriched KEGG pathway; the size of the dots represents the odds ratio; the color of the dots represents the level of a p-value. (F) PPI network of TRIM family proteins. Nodes represent proteins or protein domains, while edges represent interactions between these proteins. (G) Four overlapping genes (TRIM11, TRIM33, TRIM27, TRIM42) were expressed in case and control samples of GSE46955 data sets. Red represents the case group, and green represents the control group. (H) ROC curves of TRIM11 in GSE46955 datasets. The horizontal coordinate is a false positive fraction, and the vertical coordinate is a proper positive fraction. GO, Gene Ontology; BP, Biological process; CC, Cellular component; MF, Molecular function; KEGG, Kyoto Encyclopedia of Genes and Genomes; PPI, Protein-Protein Interaction. ROC, Receiver operating characteristic; AUC: Area under the curve; 95% CI: 95% confidence interval. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

11033_2024_10212_MOESM3_ESM.tif

Supplementary file3 (TIF 1502 KB)—Supplementary Figure 2. Interaction and functional analysis of TRIM11 target genes in the context of sepsis. (A) The UbiBrowser database highlights potential interactions between TRIM11 (center, yellow) and the top 20 target genes. (B) Venn diagram, overlap analysis between TRIM11 target genes and genes downregulated in sepsis (GSE13205 dataset). (C) Analysis of the expression levels of 14 TRIM11 target genes (BTN3A1, EN1, HDAC5, HERC1, HOXA10, HOXA13, HOXA3, HOXB9, ICAM3, LHX6, MAF, SMARCA1, TTN, ZFHX4) in the sepsis group (red) and control group (blue) of the GSE13205 dataset. (D and E) Chord plots of BP and WikiPathway enrichment analysis of TRIM11-related down-regulated genes. The color gradient represents p-values, with darker red reflecting higher significance. BP, Biological process. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

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Gan, J., Zhang, W., Pan, F. et al. TRIM11 modulates sepsis progression by promoting HOXB9 ubiquitination and inducing the NF-κB signaling pathway. Mol Biol Rep 52, 194 (2025). https://doi.org/10.1007/s11033-024-10212-5

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