PCSK9 (proprotein convertase subtilisin/kexin type 9) binds to the LDLR 
(low-density lipoprotein receptor) at the cell surface and disrupts recycling of 
the LDLR. However, PCSK9 also interacts with the LDLR in the ER (endoplasmic 
reticulum). In the present study we have investigated the role of PCSK9 for the 
transport of the LDLR from the ER to the cell membrane. A truncated LDLR 
consisting of the ectodomain (ED-LDLR) was used for these studies to avoid 
PCSK9-mediated degradation of the LDLR. The amount of secreted ED-LDLR was used 
as a measure of the amount of ED-LDLR transported from the ER. From 
co-transfection experiments of various PCSK9 and ED-LDLR plasmids, PCSK9 
increased the amount of WT (wild-type) ED-LDLR in the medium, but not of an 
ED-LDLR lacking the EGF (epidermal growth factor)-A repeat or of a Class 2a 
mutant ED-LDLR which fails to exit the ER. Mutant PCSK9s which failed to undergo 
autocatalytic cleavage or failed to exit the ER, failed to increase the amount 
of WT-ED-LDLR in the medium. These mutants also reduced the amount of WT-ED-LDLR 
intracellularly, which could partly be prevented by the proteasome inhibitor 
lactacystine. WT-ED-LDLR promoted autocatalytic cleavage of pro-PCSK9. The 
findings of the present study indicate that the binding of WT-ED-LDLR to 
pro-PCSK9 in the ER promotes autocatalytic cleavage of PCSK9, and 
autocatalytically cleaved PCSK9 acts as a chaperone to promote the exit of 
WT-ED-LDLR from the ER.