Vioprolide A exerts anti-inflammatory actions in endothelial cells through inhibiting NOP14 and downregulating KPNA2

Treatment of chronic inflammatory diseases, which are often characterized by overly activated endothelial cells (EC) and persistent leukocyte trafficking from the blood to the affected tissue, remains a major therapeutic challenge. Thus, the search for novel drugs and drug targets is an ongoing demand.

We have identified the myxobacteria-derived peptide vioprolide A (vioA) to exert anti-inflammatory actions in vivo and in ECs in vitro. VioA attenuated leukocyte trafficking through the vascular endothelium in the murine cremaster muscle and infiltration of microglia and macrophages during laser-induced murine choroidal neovascularization. Mechanistically, vioA impaired the de novo protein synthesis in ECs, thereby decreasing EC adhesion molecule and tumor necrosis factor receptor (TNFR) 1 protein levels. Importantly, downregulation of karyopherin alpha 2 (KPNA2) expression, a carrier protein needed for the translocation of the NF-ĸB subunit p65 from the cytosol to the nucleus, is a crucial part of the action of vioA causing a decreased NF-ĸB promotor activity. Knockdown experiments revealed a causal link between the cellular target of vioA, NOP14, and the anti-inflammatory actions observed.

Our results classify the natural product as unique drug lead for anti-inflammatory therapeutics.

Publikationsverlauf

Artikel online veröffentlicht:
13. Dezember 2021