Inhibition of neuraminidase-1 sialidase activity by interfering peptides impairs insulin receptor activity in vitro and glucose homeostasis in vivo.

Fiche publication

Date publication

avril 2024

Journal

The Journal of biological chemistry

Auteurs

Membres identifiés du Cancéropôle Est :
Dr BLAISE Sébastien , Dr DUCA Laurent , Dr TERRYN Christine , Dr BENNASROUNE Aline , Dr BENNASROUNE Amar

Tous les auteurs :
Toussaint K, Appert-Collin A, Vanalderwiert L, Bour C, Terryn C, Spenlé C, Van Der Heyden M, Roumieux M, Maurice P, Romier-Crouzet B, Sartelet H, Duca L, Blaise S, Bennasroune A

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/38663826

Résumé

Neuraminidases also called sialidases are glycosidases which catalyze the removal of terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides. Mammalian Neuraminidase-1 (NEU-1) participates in regulation of cell surface receptors such as insulin receptor (IR), epithelial growth factor receptor, low density lipoprotein receptor and toll like receptor 4. At the plasma membrane, NEU-1 can be associated with the elastin-binding protein and the carboxypeptidase protective protein/cathepsin A to constitute the elastin receptor complex. In this complex, NEU-1 is essential for elastogenesis, signal transduction through this receptor and for biological effects of the elastin-derived peptides on atherosclerosis, thrombosis, insulin resistance, non-alcoholic steatohepatitis and cancers. This is why research teams are developing inhibitors targeting this sialidase. Previously, we developed interfering peptides to inhibit the dimerization and the activation of NEU-1. In this study, we investigated the effects of these peptides on IR activation in vitro and in vivo. Using cellular overexpression and endogenous expression models of NEU-1 and IR (COS-7 and HepG2 cells respectively), we have shown that interfering peptides inhibit NEU-1 dimerization and sialidase activity which results in a reduction of IR phosphorylation. These results demonstrated that NEU-1 positively regulates IR phosphorylation and activation in our conditions. In vivo, biodistribution study showed that interfering peptides are well distributed in mice. Treatment of C57Bl/6 mice during eight weeks with interfering peptides induces a hyperglycemic effect in our experimental conditions. Altogether, we report here that inhibition of NEU-1 sialidase activity by interfering peptides decreases IR activity in vitro and glucose homeostasis in vivo.