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Deubiquitinase USP2 accelerates endothelial glycocalyx degradation in sepsis-induced ALI by stabilizing MTCH2

ABSTRACT: Sepsis remains a major cause of death worldwide. The lung is particularly vulnerable, and sepsis‑induced acute lung injury (ALI) carries high mortality. Endothelial glycocalyx degradation is an early event that promotes vascular leakage and inflammation, but the upstream regulators of this process are poorly understood. Here we identify ubiquitin‑specific protease 2 (USP2) as a critical driver of pulmonary endothelial glycocalyx breakdown in sepsis. USP2 expression was markedly upregulated in lung endothelial cells of septic mice and in LPS-stimulated human endothelial cells. Endothelial‑specific Usp2 knockdown protected against cecal ligation and puncture (CLP)‑induced lung injury, vascular leakage, and glycocalyx degradation. Mechanistically, USP2 directly bound to mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, and removed K27‑linked ubiquitin chains at lysine 158, thereby stabilizing MTCH2. MTCH2 was required for USP2‑mediated downregulation of syndecan‑1 (SDC1), a core glycocalyx component, and its silencing rescued SDC1 levels in USP2‑overexpressing cells. Endothelial‑specific Mtch2 knockout mice phenocopied the protective effects of USP2 deficiency, including improved survival, preserved glycocalyx structure, and reduced inflammation. These findings uncover a USP2‑MTCH2 axis that links deubiquitination to glycocalyx integrity in the pulmonary endothelium during sepsis. Targeting this interaction may offer a new therapeutic strategy for septic ALI.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336039 | GEO | 2026/06/30

REPOSITORIES: GEO

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Project description:Sepsis is a life-threatening condition with multi-organ failure caused by a dysregulated host response to infection. Among different organs susceptible to infection, the lung is the main one leading to sepsis 4. Patients with severe sepsis are at a high risk of developing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which occurs in up to 50% of patients. Myeloid C-type lectin domain family 5 member A (CLEC5A) is a pattern recognition receptor that participates in host defense against infection. Blockage of CLEC5A increased survival of mice with polymicrobial sepsis or endotoxemia, and protected the lungs against septic infection. To explore the underlying cellular and molecular mechanisms of CLEC5A in sepsis-induced lung injury, a comprehensive single-cell transcriptomics of CLEC5A-/- lungs was generated by scRNA-seq. Mice were subjected to cecal ligation and puncture (CLP), and the lungs were collected 12 h post-surgery. Single cell suspensions were prepared from lung tissues of three CLEC5A-/- mice and three WT littermates, and pooled cells from these mice were subjected to scRNA-seq processing using the 10×Genomics Chromium system. A total of 55,177 single cells, including 29,306 cells from WT lungs and 15,871 cells from CLEC5A-/- lungs, were obtained after removal of multiplets and filtration of low-quality cells. Total cells were grouped into 34 distinct clusters by Uniform Manifold Approximation and Projection, and a total of 14 distinct cell types were identified, including granulocytes, T cells, B cells, alveolar-macrophages (AM), monocytes, macrophages, natural killer T cells (NKT), mesothelium, natural killer cells (NK), endothelial cells, fibroblasts, dendritic cells (DC), epithelial cells, and smooth muscle cells (SMC).The scRNA-seq analysis implied the potential role of CLEC5A in endothelial cells regarding crosstalk with immune cells in septic lungs. Deletion of CLEC5A inhibited endothelial barrier dysfunction induced by sepsis, and decreased leukocyte-endothelial adhesion and transendothelial migration. The role of CLEC5A in pulmonary endothelial cells and the barrier function is identified for the first time, which contributes to the regulation of immunity/inflammation in the lungs under septic infection. This work extends the therapeutic potential of targeting CLEC5A in sepsis-induced endothelial barrier dysfunction and lung injury.

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Deubiquitinase USP2 accelerates endothelial glycocalyx degradation in sepsis-induced ALI by stabilizing MTCH2

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