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Apoprotein B: quality control early and late in the secretory pathway for this atherogenic protein
Author(s) -
Fisher Edward A,
Ginsberg Henry N,
Ron David,
Williams Kevin J,
Brodsky Jeffrey L
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.469.1
Subject(s) - endoplasmic reticulum associated protein degradation , apolipoprotein b , chaperone (clinical) , very low density lipoprotein , microbiology and biotechnology , proteasome , chemistry , golgi apparatus , lipoprotein , biochemistry , unfolded protein response , biology , endoplasmic reticulum , cholesterol , pathology , medicine
Apoprotein B (apoB100) is required for the formation of VLDL, the precursor of LDL, the plasma level of which is a strong risk factor for atherosclerosis and coronary artery disease (CAD). It is an exceptionally large (>4000 aa) and hydrophobic protein. As the nascent polypeptide is translocating across the ER, if lipids are not transferred to stabilize its conformation, we and others have shown that like other abnormally folded proteins in the ER, its quality control is governed by ER‐associated ub‐proteasome degradation (ERAD). Using a combination of systems from yeast to genetically modified mice, we and our collaborators have shown apoB100 ERAD to involve chaperone and chaperone‐like molecules, such as Hsp70, 90, 110, and p58. The full assembly of VLDL does not occur until the Golgi. We have discovered that nascent particles (“pre‐VLDL”) that do not complete this maturation process (e.g., under the influence of certain dietary fatty acids), are subject to a late stage quality control process mediated by autophagy. In summary, the production of apoB100‐lipoproteins, whose plasma levels correlate with the risk of CAD, is determined in part by quality control processes that recognize features of the protein specific to its stage of assembly and that are separated between the ER and Golgi compartments.