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 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.
Fisher
E A
EA
Laboratory of Lipoprotein Research, Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
Zhou
M
M
Mitchell
D M
DM
Wu
X
X
Omura
S
S
Wang
H
H
Goldberg
A L
AL
Ginsberg
H N
HN
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000378:metabolism*; D016227:Benzoquinones; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D047029:Lactams, Macrocyclic; D008715:Methionine / Q000378:metabolism; D009097:Multienzyme Complexes / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D014452:Ubiquitins / Q000502:physiology*
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009097:Multienzyme Complexes; D011809:Quinones; D014452:Ubiquitins; D017828:Rifabutin; C020754:herbimycin; D008715:Methionine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex