title: Secreted PCSK9 promotes LDL receptor degradation independently of proteolytic activity.
abstract: 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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, U.S.A. junli@gnf.org
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Christine
authors.initials: C
authors.lastname: Tumanut
authors.forename: Julie-Ann
authors.initials: JA
authors.lastname: Gavigan
authors.forename: Waan-Jeng
authors.initials: WJ
authors.lastname: Huang
authors.forename: Eric N
authors.initials: EN
authors.lastname: Hampton
authors.forename: Rachelle
authors.initials: R
authors.lastname: Tumanut
authors.forename: Ka Fai
authors.initials: KF
authors.lastname: Suen
authors.forename: John W
authors.initials: JW
authors.lastname: Trauger
authors.forename: Glen
authors.initials: G
authors.lastname: Spraggon
authors.forename: Scott A
authors.initials: SA
authors.lastname: Lesley
authors.forename: Gene
authors.initials: G
authors.lastname: Liau
authors.forename: David
authors.initials: D
authors.lastname: Yowe
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harris
mesh_terms: 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*
chemical_list: D011973:Receptors, LDL; D012694:Serine; D012697:Serine Endopeptidases