Variation in the human ApoB signal peptide modulates ApoB17 translocation.
The functional effects of the common 27- or 24-amino-acid (aa) variants in the human apoB signal peptide (SP) on intracellular and secreted apoB17 were investigated in vitro. Only in the presence of oleate was a significant difference in intracellular and secreted SP27-B17 compared to SP24-B17 observed (P = 0.01 and P < 0.0007, respectively), although in the presence or absence of oleate mRNA levels from the two constructs were similar. After fractionation, oleate treatment enhanced microsomal SP27-B17 by 150% (P < 0.0005) with a modest but significant effect on SP24-B17 (32% P = 0.007). Oleate stimulated SP24-B17 accumulation in the nonmicrosomal fraction. The data suggest that the presence of oleate leads to inefficient translocation of the 24-amino-acid signal peptide, possibly resulting in increased retrograde translocation into the cytoplasm and reduced intracellular and secreted levels compared to the "wildtype" 27 aa SP. This implies a direct role of the SP variants in the regulation of apoB intracellular metabolism.
Benhizia
F
F
Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, London, WC1E 6JJ, United Kingdom.
Ginsberg
H N
HN
Humphries
S E
SE
Talmud
P J
PJ
D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002458:Cell Fractionation; D003600:Cytosol / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology; D011110:Polymorphism, Genetic; D021382:Protein Sorting Signals / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured
D001055:Apolipoproteins B; D021382:Protein Sorting Signals; D012333:RNA, Messenger; C416027:apolipoprotein b-17; D019301:Oleic Acid