title: TNF-α regulates the proteolytic degradation of ST6Gal-1 and endothelial cell-cell junctions through upregulating expression of BACE1.
abstract: Endothelial dysfunction and monocyte adhesion to vascular endothelial cells are two critical steps in atherosclerosis development, and emerging evidence suggests that protein sialylation is involved in these processes. However, the mechanism underlying this phenomenon remains incompletely elucidated. In this study, we demonstrated that treatment with the proinflammatory cytokine TNF-α disrupted vascular endothelial cell-cell tight junctions and promoted monocyte endothelial cell adhesion. Western blotting and Sambucus nigra lectin (SNA) blotting analyses revealed that TNF-α treatment decreased α-2, 6-sialic acid transferase 1 (ST6Gal-I) levels and downregulated VE-Cadherin α-2, 6 sialylation. Further analysis demonstrated that TNF-α treatment upregulated β-site amyloid precursor protein enzyme 1 (BACE1) expression, thus resulting in sequential ST6Gal-I proteolytic degradation. Furthermore, our results revealed that PKC signaling cascades were involved in TNF-α-induced BACE1 upregulation. Together, these results indicated that the proinflammatory cytokine TNF-α impairs endothelial tight junctions and promotes monocyte-endothelial cell adhesion by upregulating BACE1 expression through activating PKC signaling and sequentially cleaving ST6Gal-I. Thus, inhibition of BACE1 expression may be a new approach for treating atherosclerosis.
authors.affiliation: Institute of Life Science, Chongqing Medical University, Chongqing 400016, P. R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Deng
authors.affiliation: Institute of Life Science, Chongqing Medical University, Chongqing 400016, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Life Science, Chongqing Medical University, Chongqing 400016, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Life Science, Chongqing Medical University, Chongqing 400016, P. R. China.
authors.forename: Linmu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institute of Life Science, Chongqing Medical University, Chongqing 400016, P. R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D002470:Cell Survival; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D059748:Proteolysis; D012799:Sialyltransferases / Q000378:metabolism*; D015398:Signal Transduction; D019108:Tight Junctions / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism*; D015854:Up-Regulation; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D053829:Amyloid Precursor Protein Secretases; D015703:Antigens, CD; D016282:Aspartic Acid Endopeptidases; D012799:Sialyltransferases; D014409:Tumor Necrosis Factor-alpha; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase; C509280:BACE1 protein, human