Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control

doi:10.1073/pnas.0707460104

Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control

*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;
^†Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021;
^‡Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, ON, Canada K1Y 4W7;
^§Departments of Biochemistry, Microbiology and Immunology, Medicine, and Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5; and
^¶Department of Medicine, Division of Endocrinology, Diabetes, and Metabolic Diseases, Thomas Jefferson University, Philadelphia, PA 19107

Communicated by Jan L. Breslow, The Rockefeller University, New York, NY, August 7, 2007. (received for review February 7, 2007)

Abstract

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.

Footnotes

^‖To whom correspondence may be addressed. E-mail: k_williams{at}mail.jci.tju.edu or edward.fisher{at}med.nyu.edu
Author contributions: M.P., F.R.M., K.J.W., and E.A.F. designed research; M.P., V.M., S.P., U.A., and S.X.L. performed research; C.S.G. and Z.Y. contributed new reagents/analytic tools; M.P., K.J.W., and E.A.F. analyzed data; and M.P., K.J.W., and E.A.F. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0707460104/DC1.