Secreted PCSK9 promotes LDL receptor degradation independently of proteolytic activity.
PCSK9 (proprotein convertase subtilisin/kexin 9) is a secreted serine protease that regulates cholesterol homoeostasis by inducing post-translational degradation of hepatic LDL-R [LDL (low-density lipoprotein) receptor]. Intramolecular autocatalytic processing of the PCSK9 zymogen in the endoplasmic reticulum results in a tightly associated complex between the prodomain and the catalytic domain. Although the autocatalytic processing event is required for proper secretion of PCSK9, the requirement of proteolytic activity in the regulation of LDL-R is currently unknown. Co-expression of the prodomain and the catalytic domain in trans allowed for production of a catalytically inactive secreted form of PCSK9. This catalytically inactive PCSK9 was characterized and shown to be functionally equivalent to the wild-type protein in lowering cellular LDL uptake and LDL-R levels. These findings suggest that, apart from autocatalytic processing, the protease activity of PCSK9 is not necessary for LDL-R regulation.
Li
Jun
J
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, U.S.A. junli@gnf.org
Tumanut
Christine
C
Gavigan
Julie-Ann
JA
Huang
Waan-Jeng
WJ
Hampton
Eric N
EN
Tumanut
Rachelle
R
Suen
Ka Fai
KF
Trauger
John W
JW
Spraggon
Glen
G
Lesley
Scott A
SA
Liau
Gene
G
Yowe
David
D
Harris
Jennifer L
JL
D002460:Cell Line; D006801:Humans; D009154:Mutation / Q000235:genetics; D011973:Receptors, LDL / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
D011973:Receptors, LDL; D012694:Serine; D012697:Serine Endopeptidases