Life sciences · 2025
The E3 ubiquitin ligase midline 1 reduces the intrinsic antibacterial activity of hepatocytes by promoting HRG degradation during sepsis.
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Shu Junjie, Ma Wei, Liu Haoru, Dai Haisu, Zhang Hao, Gao Rui, Yang Xue, Tang Wanqi, Huang Yang, Ma Xiaoyuan, Liang Huaping, Yang Xia
Аннотация
AIMS: The ubiquitination system in hepatocytes and its direct role in antibacterial defense during sepsis remain poorly understood. This study investigated the mechanism by which the E3 ubiquitin ligase Midline 1 (Mid1) regulates the degradation of histidine-rich glycoprotein (HRG) during bacterial infection, and a proof-of-concept approach was proposed to block Mid1 and relieve hepatic sepsis.
MATERIAL AND METHODS: Transcriptomic analysis of livers from a mouse cecal ligation and puncture (CLP) model was used to reveal changes in the global ubiquitination and Mid1 level. Immunoprecipitation, coupled with mass spectrometry, and native PAGE, was used to assess the proteins that bind to Mid1. The therapeutic effects of Mid1 in vivo were evaluated through hepatocyte-specific siRNAs and inhibitors.
KEY FINDINGS: Mid1 was significantly upregulated in hepatocytes from both CLP mice and patients with acute infection, accompanied by increased global ubiquitination. Inhibiting Mid1 in hepatocytes enhanced their antibacterial capacity and reduced infection-induced cellular damage in cellulo and in vivo experiments. Mid1 overexpression increased bacterial survival in AML12 hepatocyte cell lines. Mechanistically, Mid1 physically directly binds the HRG and targets it for ubiquitin-proteasomal degradation. Crucially, HRG, identified as a novel Mid1 substrate, is critical for antibacterial defense-blocking HRG abolished the protective effects of Mid1 knockdown. Hepatocyte-specific Mid1 siRNA and DPP4 inhibitors improved systemic outcomes and survival in septic mice.
SIGNIFICANCE: This study highlights that the Mid1-HRG ubiquitination axis is a critical regulator of sepsis progression, suggesting a novel therapeutic strategy to augment the liver's intrinsic antibacterial activity.
MATERIAL AND METHODS: Transcriptomic analysis of livers from a mouse cecal ligation and puncture (CLP) model was used to reveal changes in the global ubiquitination and Mid1 level. Immunoprecipitation, coupled with mass spectrometry, and native PAGE, was used to assess the proteins that bind to Mid1. The therapeutic effects of Mid1 in vivo were evaluated through hepatocyte-specific siRNAs and inhibitors.
KEY FINDINGS: Mid1 was significantly upregulated in hepatocytes from both CLP mice and patients with acute infection, accompanied by increased global ubiquitination. Inhibiting Mid1 in hepatocytes enhanced their antibacterial capacity and reduced infection-induced cellular damage in cellulo and in vivo experiments. Mid1 overexpression increased bacterial survival in AML12 hepatocyte cell lines. Mechanistically, Mid1 physically directly binds the HRG and targets it for ubiquitin-proteasomal degradation. Crucially, HRG, identified as a novel Mid1 substrate, is critical for antibacterial defense-blocking HRG abolished the protective effects of Mid1 knockdown. Hepatocyte-specific Mid1 siRNA and DPP4 inhibitors improved systemic outcomes and survival in septic mice.
SIGNIFICANCE: This study highlights that the Mid1-HRG ubiquitination axis is a critical regulator of sepsis progression, suggesting a novel therapeutic strategy to augment the liver's intrinsic antibacterial activity.