Dataset Information

SUMOylation proteomic analysis in mouse liver

ABSTRACT: Protein SUMOylation is crucial in both physiological and pathological contexts, but its role in acute liver injury is poorly understood. We found that SENP3, a SUMO2/3 protease, rapidly accumulates in hepatocytes around the pericentral vein zone within 2 hours of CCl₄-induced liver injury in mice. Knockout of SENP3 in hepatocytes worsens liver damage and promotes pyroptosis. The project demonstrated that SENP3 inhibits hepatocyte pyroptosis through a finely tuned mechanism involving post-translational modifications and the stabilization of key biomolecules HNRNPL.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Jie Yang

LAB HEAD: Jie Yang

PROVIDER: PXD065419 | Pride | 2026-02-09

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	FE584LPSU_C1_B3_1_20610.d.zip	Other
	FE584LPSU_C2_B4_1_20612.d.zip	Other
	FE584LPSU_N1_B1_1_20606.d.zip	Other
	FE584LPSU_N4_B2_1_20608.d.zip	Other
	combined.zip	Other

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Publications

SENP3 protects hepatocyte from pyroptosis during acute liver injury through deSUMOylation of HNRNPL.

Xiong Xinyuan X Zhi Yang Y Yang Nan N Zhao Wenzhen W Wang Shu S Zhu Huiqin H Tang Jieting J Yi Jing J Sun Xuxu X Yang Jie J

iScience 20250707 8

Protein SUMOylation is crucial in both physiological and pathological contexts, but its role in acute liver injury (ALI) is poorly understood. We found that SENP3, a SUMO2/3 protease, rapidly accumulates in hepatocytes around the pericentral vein zone within 2 h of carbon tetrachloride (CCl<sub>4</sub>)-induced liver injury in mice. Knockout of SENP3 in hepatocytes worsens liver damage and promotes pyroptosis. Mechanistically, SENP3 interacts with the RNA-binding protein HNRNPL, facilitating its ...[more]

PMID: 40792025

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Project description:Background and Aims: The activation of stimulator of interferon genes (STING) and NOD-like receptors protein 3 (NLRP3) inflammasomes-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnection between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown and is the focus of this study. Approach and Results: Liver fibrosis was induced in Sting knockout, Gasdermin D (Gsdmd) knockout mice, and in mice with hepatocyte-specific Nlrp3 deletion. RNA-sequencing, metabolomics, epigenetic compound screening system, and chromatin immunoprecipitation were utilized. STING and NLRP3 inflammasome signaling pathways were activated in cirrhotic livers but were suppressed by Sting knockout. Sting knockout also ameliorated hepatic pyroptosis, inflammation, and fibrosis in the murine cirrhotic model. In vitro, STING induced pyroptosis in primary murine hepatocytes via activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) were identified to regulate NLRP3 expression in STING-overexpressed AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhanced interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promoted STING-induced Nlrp3 transcription in hepatocytes. The RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes showed that metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gsdmd knockout attenuated hepatic pyroptosis, inflammation, and fibrosis in murine cirrhotic models. Conclusions: This study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.

Project description:Background: Evidence has recently accumulated suggesting that mature hepatocytes have the unique capacity to autonomously decide their replication fate. The molecular mechanism by which hepatocytes switch from an essentially quiescent state to rapidly proliferation after liver injury is not fully understood. To provide molecular insights into the self-renewal of mature hepatocytes, we have applied an ex vivo liver slice culture system. Results: After liver injury, activation of p38 and Erk1/2 began in mature hepatocytes within 5 min. Erk1/2 was activated at the edge of the cut as well as on the surface of liver slices. The number of hepatocytes that contain activated Erk1/2 increased within 1 h and then decreased. Concomitantly, immediate early genes (IEGs), such as Jun, early gene response 1 (Egr1) and Myc were induced and Ki67 positive hepatocytes appeared 24 h after liver injury in the slices. In agreement with in vivo studies, transcriptome analysis using 2 h slice culture reveals that 63% of upregulated genes were downstream of lipopolysaccharide (LPS) stimulation which induces interleukin 6 (IL 6) or tumor necrosis factor (TNF) alpha pathways. Furthermore, circadian clock regulator, such as members of the basic helix-loop-helix family, Bhlhe40 and Bhlhe41, were highly upregulated for 4 h after injury. Although upon injury Jun or Egr1 were induced in liver slices from proliferation-defective liver, no circadian clock regulator genes were upregulated. Moreover, using an in vitro cell culture system we show that Bhlhe40 is required for the G0-G1 transition. Conclusion: Our data suggest that the circadian clock regulator, Bhlhe40, is involved in the G0-G1 transition. An ex vivo system using normal and proliferation defective KO liver is a useful tool for identification of genes that trigger cell proliferation shortly after liver injury. This method may also be applied for measurement of the liver regeneration potential of individual livers at the priming phase. In one dual-color microarray hybridization, mRNA expression changes after 2h ex vivo incubation of liver slices were examined.