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(Received for publication, April 4, 1997)
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From the Apolipoprotein B (apoB) is the major protein
component of atherogenic lipoproteins of hepatic origin. In HepG2
cells, the standard cell culture model of human hepatic lipoprotein
metabolism, there is a limited availability of core lipids in the
endoplasmic reticulum for association with nascent apoB. Under these
conditions, apoB is partially translocated, interacts with cytosolic
Hsp70, and undergoes rapid degradation. We show that increasing the
expression of Hsp70 in HepG2 cells promotes apoB degradation. In
addition, apoB is polyubiquitinated and its degradation both normally
and after Hsp70 induction is blocked by inhibitors of the proteasome. The apoB that accumulates after proteasome inhibition is endoplasmic reticulum-associated and can be assembled into lipoproteins and secreted if new lipid synthesis is stimulated. Thus, apoB is the first
example of a wild-type mammalian protein whose secretion is regulated
by degradation in the cytosol via the ubiquitin-proteasome pathway.
Furthermore, targeting of this secretory protein to the proteasome is
regulated by the molecular chaperone Hsp70 and the availability of
apoB's lipid-ligands.
Laboratory of Lipoprotein Research,
Cardiovascular Institute, Mount Sinai School of Medicine, New York,
New York 10029, the Department of Medicine, College of
Physicians and Surgeons, Columbia University, New York, New York
10032, ** The Kitasato Institute, Tokyo 108, Japan, and the
Department of Cell Biology, Harvard
Medical School, Boston, Massachusetts 02115
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