THE DEGRADATION OF APOLIPOPROTEIN B100 IS MEDIATED BY THE UBIQUITIN-PROTEASOME PATHWAY AND INVOLVES HEAT-SHOCK-PROTEIN-70

Apolipoprotein B (apoB) is the major protein component of atherogenic lipoproteins of hepatic origin, In HepG2 cells, the standard cell cult ure model of human hepatic lipoprotein metabolism, there is a limited availability of core lipids in the endoplasmic reticulum for associati on with nascent apoB. Under these conditions, apoB is partially transl ocated, interacts with cytosolic Hsp70, and undergoes rapid degradatio n. We show that increasing the expression of Hsp70 in HepG2 cells prom otes apoB degradation. In addition, apoB is polyubiquitinated and its degradation both normally and after Hsp70 induction is blocked by inhi bitors of the proteasome. The apoB that accumulates after proteasome i nhibition is endoplasmic reticulum-associated and can be assembled int o lipoproteins and secreted if new lipid synthesis is stimulated. Thus , apoB is the first example of a wild-type mammalian protein whose sec retion is regulated by degradation in the cytosol via the ubiquitin-pr oteasome pathway. Furthermore, targeting of this secretory protein to the proteasome is regulated by the molecular chaperone Hsp70 and the a vailability of apoB's lipid-ligands.