Autophagy protein ATG7 is a critical regulator of endothelial cell inflammation and permeability.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Autophagy* ; Cell Membrane Permeability*; Autophagy-Related Protein 7/*metabolism ; Endothelium, Vascular/*immunology ; Inflammation/*immunology ; NF-kappa B/*metabolism ; Pulmonary Artery/*immunology; Autophagy-Related Protein 7/genetics ; Cells, Cultured ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Gene Expression Regulation ; Humans ; Inflammation/chemically induced ; Inflammation/metabolism ; NF-kappa B/genetics ; Phosphorylation ; Pulmonary Artery/drug effects ; Pulmonary Artery/metabolism ; Signal Transduction ; Thrombin/pharmacology

Endothelial cell (EC) inflammation and permeability are critical pathogenic mechanisms in many inflammatory conditions including acute lung injury. In this study, we investigated the role of ATG7, an essential autophagy regulator with no autophagy-unrelated functions, in the mechanism of EC inflammation and permeability. Knockdown of ATG7 using si-RNA significantly attenuated thrombin-induced expression of proinflammatory molecules such as IL-6, MCP-1, ICAM-1 and VCAM-1. Mechanistic study implicated reduced NF-κB activity in the inhibition of EC inflammation in ATG7-silenced cells. Moreover, depletion of ATG7 markedly reduced the binding of RelA/p65 to DNA in the nucleus. Surprisingly, the thrombin-induced degradation of IκBα in the cytosol was not affected in ATG7-depleted cells, suggesting a defect in the translocation of released RelA/p65 to the nucleus in these cells. This is likely due to suppression of thrombin-induced phosphorylation and thereby inactivation of Cofilin1, an actin-depolymerizing protein, in ATG7-depleted cells. Actin stress fiber dynamics are required for thrombin-induced translocation of RelA/p65 to the nucleus, and indeed our results showed that ATG7 silencing inhibited this response via inactivation of Cofilin1. ATG7 silencing also reduced thrombin-mediated EC permeability by inhibiting the disassembly of VE-cadherin at adherens junctions. Together, these data uncover a novel function of ATG7 in mediating EC inflammation and permeability, and provide a mechanistic basis for the linkage between autophagy and EC dysfunction.

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R01 HL130870 United States HL NHLBI NIH HHS; P30 ES001247 United States ES NIEHS NIH HHS; R01 HL138538 United States HL NHLBI NIH HHS; R01 GM130463 United States GM NIGMS NIH HHS; T32 ES007026 United States ES NIEHS NIH HHS

0 (NF-kappa B)
EC 3.4.21.5 (Thrombin)
EC 6.2.1.45 (ATG7 protein, human)
EC 6.2.1.45 (Autophagy-Related Protein 7)

Date Created: 20200815 Date Completed: 20210111 Latest Revision: 20240428

20240428

PMC7426828

10.1038/s41598-020-70126-7

32792588