CELL SURFACE NUCLEOLIN MEDIATES ADAMTS5- INDUCED APOPTOSIS IN ENDOTHELIAL CELLS

Abstract

A Disintegrin and Metalloproteinase with ThromboSpondin motif 5 (ADAMTS5), was previously identified by our lab as an anti-angiogenic/tumorigenic protein. Similarly, the autocatalytically cleaved truncate of ADAMTS5 (TS5-p45) inhibits angiogenesis and induces endothelial cell (EC) apoptosis. However, how ADAMTS5 triggers EC apoptosis remains unclear. In this work, I identified that EC surface nucleolin (NCL) is a novel high-affinity receptor for ADAMTS5. Upon interacting with surface NCL, TS5-p45 is internalized through clathrin- and caveolin-dependent endocytosis and trafficked to the nucleus via intact late endosomes (LEs). LE-mediated nuclear trafficking is required for TS5-p45-induced apoptosis. I also demonstrated that cell surface NCL shuttles extracellular TS5-p45 to the nucleus via nuclear import mechanism. Furthermore, I identified a set of apoptosis-related genes that might be involved in TS5-p45-induced apoptosis. This work identifies the critical role of cell surface NCL-mediated nuclear trafficking for ADAMTS5-induced EC apoptosis. Hence, ADAMTS5 can be used in NCL-targeted anti-angiogenic/tumorigenic therapy.