Presecretory degradation of apolipoprotein[a] is mediated by the proteasome pathway

Plasma levels of atherogenic lipoprotein [a] (Lp[a]) vary over a 1000-fold range and are largely determined by the gene for its unique glycoprotein, a polipoprotein [a] (apo[a]). The apo[a] locus comprises more than 100 allele s, encoding proteins from <300 to >800 kDa. Using primary baboon hepatocyte cultures, we previously demonstrated that differences in the secretion eff iciency of apo[a] allelic variants contribute to the variation in plasma Lp [a] levels, In the current study, we investigated the mechanism of apo[a] p resecretory degradation, The proteasome inhibitors, acetyl-leucyl-leucyl-no rleucinal and lactacystin, prevented apo[a] degradation and increased apo[a ] secretion, Transfection with an HA-tagged ubiquitin construct demonstrate d the accumulation of ubiquitinated apo[a] in the presence of lactacystin. These results suggest a role for the cytoplasmic proteasome in apo[a] prote olysis, Apo[a] that accumulated intracellularly in the presence of lactacys tin remained sensitive to endo-B-N-glucosaminidase H, and apo[a] degradatio n was reversibly inhibited by brefeldin A, suggesting that transport to a p ost-endoplasmic reticulum (ER) pre-medial Golgi compartment is required for apo[a] degradation, Newly synthesized apo[a] bound to the ER chaperone cal nexin and conditions that enhanced this interaction prevented apo[a] degrad ation, suggesting that calnexin can protect apo[a] from proteolysis. These studies provide further support for the role of the proteasome in endoplasm ic reticulum quality control, and expand this role to one that influences p lasma levels of the atherogenic lipoprotein Lp[a].