Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: a pathway for late-stage quality control.
Hepatic secretion of apolipoprotein-B (apoB), the major protein of atherogenic lipoproteins, is regulated through posttranslational degradation. We reported a degradation pathway, post-ER pre secretory proteolysis (PERPP), that is increased by reactive oxygen species (ROS) generated within hepatocytes from dietary polyunsaturated fatty acids (PUFA). We now report the molecular processes by which PUFA-derived ROS regulate PERPP of apoB. ApoB exits the ER; undergoes limited oxidant-dependent aggregation; and then, upon exit from the Golgi, becomes extensively oxidized and converted into large aggregates. The aggregates slowly degrade by an autophagic process. None of the oxidized, aggregated material leaves cells, thereby preventing export of apoB-lipoproteins containing potentially toxic lipid peroxides. In summary, apoB secretory control via PERPP/autophagosomes is likely a key component of normal and pathologic regulation of plasma apoB levels, as well as a means for remarkably late-stage quality control of a secreted protein.
Pan
Meihui
M
Departments of Medicine, Leon H. Charney Division of Cardiology, and Cell Biology and the Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY 10016, USA.
Maitin
Vatsala
V
Parathath
Sajesh
S
Andreo
Ursula
U
Lin
Sharron X
SX
St Germain
Carly
C
Yao
Zemin
Z
Maxfield
Frederick R
FR
Williams
Kevin Jon
KJ
Fisher
Edward A
EA
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D001343:Autophagy; D002478:Cells, Cultured; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017382:Reactive Oxygen Species
D001055:Apolipoproteins B; D005231:Fatty Acids, Unsaturated; D017382:Reactive Oxygen Species; D010447:Peptide Hydrolases