Cell surface nucleolin is a novel ADAMTS5 receptor mediating endothelial cell apoptosis

• DOI: 10.1038/s41419-022-04618-x
• Publication Date: 2022-02-23T07:23:52Z
• Authors: Dogan Can Kirman; Bhuvanasundar Ren...; Wai Kit Chui; Ming Wei Chen; Neslihan Arife Kaya; Ruowen Ge
• Keywords: Nucleolin

Abstract A Disintegrin and Metalloproteinase with ThromboSpondin motif (ADAMTS) 5 functions as an anti-angiogenic anti-cancer protein independent of its metalloproteinase activity. Both full-length ADAMTS5 TS5-p45, the autocatalytically cleaved C-terminal 45 kDa truncate ADAMTS5, inhibits angiogenesis, induces endothelial cell (EC) apoptosis. However, how triggers EC apoptosis remains unclear. This work shows that caspase-8 (Cas-8) caspase-9 (Cas-9) are involved in TS5-p45-induced We identify surface nucleolin (NCL) a novel high-affinity receptor for TS5-p45 ECs, mediating TS5-p45’s binding pro-apoptotic function. show central RNA-binding domain (RBD) NCL is essential sufficient to TS5-p45. Upon interacting NCL, internalized through clathrin- caveolin-dependent endocytosis trafficked nucleus via late endosomes (LEs). demonstrate nuclear trafficking important activity disruption LE membrane integrity endosomolytic peptide suppressed both Through biotinylation, we revealed shuttles extracellular mediate Furthermore, blocking importin α1/ß1 hindered suggesting involvement importing machinery this translocation. RNA-seq identified many apoptosis-related genes differentially expressed at least two-fold TS5-p45-treated 10 them qRT-PCR-validated these potentially contributing TS5-p45-NCL-induced Altogether, our identifies demonstrates critical role NCL-mediated internalization ADAMTS5-induced These findings reveal mechanistic insights secreted angiogenesis inhibition.