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The endonuclease activity of MCPIP1 controls the neoplastic transformation of epithelial cells via the c-Met/CD44 axis.
Cell Commun Signal
January 2025
Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
The RNase activity of MCPIP1 is essential for regulating cellular homeostasis, proliferation, and tumorigenesis. Our study elucidates the effects of downregulation of MCPIP1 expression and an RNase-inactivating mutation (D141N) on normal epithelial kidney cells, indicating that MCPIP1 expression is a key factor that suppresses neoplastic transformation. We observed that either expression downregulation or mutation of MCPIP1 significantly increased its clonogenicity and altered the expression of cancer stem cell (CSC) markers and factors involved in epithelial-to-mesenchymal transition (EMT).
View Article and Find Full Text PDFSmall molecule inhibits KCNQ channels with a non-blocking mechanism.
Nat Chem Biol
January 2025
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Voltage-gated ion channels (VGICs) are crucial targets for neuropsychiatric therapeutics owing to their role in controlling neuronal excitability and the established link between their dysfunction and neurological diseases, highlighting the importance of identifying modulators with distinct mechanisms. Here we report two small-molecule modulators with the same chemical scaffold, Ebio2 and Ebio3, targeting a potassium channel KCNQ2, with opposite effects: Ebio2 acts as a potent activator, whereas Ebio3 serves as a potent and selective inhibitor. Guided by cryogenic electron microscopy, patch-clamp recordings and molecular dynamics simulations, we reveal that Ebio3 attaches to the outside of the inner gate, employing a unique non-blocking inhibitory mechanism that directly squeezes the S6 pore helix to inactivate the KCNQ2 channel.
View Article and Find Full Text PDFCompetitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1.
J Lipid Res
January 2025
Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark. Electronic address:
Movement of lipoprotein lipase (LPL) from myocytes or adipocytes to the capillary lumen is essential for intravascular lipolysis and plasma triglyceride homeostasis-low LPL activity in the capillary lumen causes hypertriglyceridemia. The trans-endothelial transport of LPL depends on ionic interactions with GPIHBP1's intrinsically disordered N-terminal tail, which harbors two acidic clusters at positions 5-12 and 19-30. This polyanionic tail provides a molecular switch that controls LPL detachment from heparan sulfate proteoglycans (HSPGs) by competitive displacement.
View Article and Find Full Text PDFImpact of SARS-CoV-2 inactivated vaccine on symptoms following omicron variant breakthrough infection.
Vaccine
January 2025
Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing 100191, China.. Electronic address:
The SARS-CoV-2 Omicron variant and its sublineages continue to circulate widely. Clinical outcomes with this variant differ among individuals, primarily influenced by host immunity. Previous studies have explored the relationship between immune responses and severe diseases in infected or convalescent patients.
View Article and Find Full Text PDFPIM1 enhances insulin secretion and inhibits ferroptosis of high glucose-induced pancreatic β-cells through strengthening PINK1/Parkin-mediated mitophagy via inactivating JNK/p38 signaling pathway.
Tissue Cell
January 2025
Department of Endocrinology, Fuyang Cancer Hospital, Fuyang, Anhui Province 236000, PR China. Electronic address:
Background: Diabetes mellitus (DM), a chronic metabolic disease, is characterized by long-term hyperglycemia resulting from the defect of insulin production and insulin resistance. The damage and dysfunction of pancreatic β-cells is a main link in DM development.
Methods: In this work, pancreatic β-cell line INS-1E cells were exposed to 30 mM glucose for 48 h to construct an in vitro DM model.
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