Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase

Lipoprotein lipase and the receptor-associated protein (RAP) bind to overla pping sites on the low density Lipoprotein receptor-related protein/alpha(2 )-macroglobulin receptor (LRP), We have investigated if lipoprotein lipase interacts with the RAP binding but structurally distinct receptor sortilin/ neurotensin receptor-3, We show, by chemical cross-linking and surface plas mon resonance analysis, that soluble sortilin binds lipoprotein lipase with an affinity similar to that of LRP. The binding was inhibited by heparin a nd RAP and by the newly discovered sortilin ligand neurotensin. In S-35-lab eled 3T3-L1 adipocytes treated with the cross-linker dithiobis(succinimidyl propionate), lipoprotein lipase-containing complexes were isolated by anti -sortilin antibodies. To elucidate function in cells, sortilin-negative Chi nese hamster ovary cells were transfected with full-length sortilin and sho wn to express about 8% of the receptors on the cell surface. These cells de graded I-125-labeled lipoprotein lipase much faster than the wildtype cells . The degradation was inhibited by unlabeled lipoprotein lipase, indicating a saturable pathway, and by RAP and heparin. Moreover, inhibition by the w eak base chloroquine suggested that degradation occurs in an acidic vesicle compartment. The results demonstrate that sortilin is a multifunctional re ceptor that binds lipoprotein lipase and, when expressed on the cell. surfa ce, mediates its endocytosis and degradation.