Degradation of the LDL receptors by PCSK9 is not mediated by a secreted protein acted upon by PCSK9 extracellularly.

2.50
Hdl Handle:
http://hdl.handle.net/10143/41593
Title:
Degradation of the LDL receptors by PCSK9 is not mediated by a secreted protein acted upon by PCSK9 extracellularly.
Authors:
Holla, Øystein Lunde; Cameron, Jamie; Berge, Knut Erik; Ranheim, Trine; Leren, Trond P
Citation:
BMC cell biology 2007, 8:9
Additional Links:
http://www.biomedcentral.com/1471-2121/8/9

Full metadata record

DC FieldValue Language
dc.contributor.authorHolla, Øystein Lunde-
dc.contributor.authorCameron, Jamie-
dc.contributor.authorBerge, Knut Erik-
dc.contributor.authorRanheim, Trine-
dc.contributor.authorLeren, Trond P-
dc.date.accessioned2008-11-29T15:03:10Z-
dc.date.available2008-11-29T15:03:10Z-
dc.date.issued2007-03-01-
dc.identifier.citationBMC cell biology 2007, 8:9en
dc.identifier.issn1471-2121-
dc.identifier.pmid17328821-
dc.identifier.doi10.1186/1471-2121-8-9-
dc.identifier.urihttp://hdl.handle.net/10143/41593-
dc.description.abstractBACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) post-transcriptionally degrades the low density lipoprotein receptors (LDLR). However, it is unknown whether PCSK9 acts directly on the LDLR or if PCSK9 activates another protein that in turn causes degradation of the LDLR. RESULTS: We have transiently transfected HepG2 cells with wild-type and mutant D374Y-PCSK9 plasmids to study the effect of the conditioned medium on the LDLR of untransfected HepG2 cells. The ability of the conditioned medium to reduce the internalization of LDL was abolished by removal of recombinant PCSK9 from the conditioned medium by affinity chromatography. Thus, PCSK9 is the only factor in the conditioned medium able to mediate degradation of the LDLR. Moreover, fractionation of the conditioned medium by gel filtration showed that the ability of the fractions to reduce the internalization of LDL, closely paralleled the amount of D374Y-PCSK9 in the fractions. Incubation of a secreted, truncated LDLR without cytoplasmic and transmembrane domains, as well as membrane fractions from HepG2 cells, with conditioned medium containing PCSK9, did not reduce the amount of LDLR as determined by western blot analysis. Thus, the LDLR is not degraded by PCSK9 on the cell surface. The LDLR of HepG2 cells incubated with conditioned medium was protected from PCSK9-mediated degradation by the addition of nocodazole or ammonium chloride, but was not protected when the conditioned medium was made hypertonic. These findings indicate that the intracellular degradation of the LDLR involves intracellular transport along microtubules, an acidic intracellular compartment and that it occurs even when endocytosis through clathrin-coated pits has been blocked. CONCLUSION: Degradation of the LDLR by PCSK9 is not mediated by a secreted protein acted upon by PCSK9 extracellularly. Also the PCSK9-mediated degradation of the LDLR does not take place on the cell surface. Rather, the PCSK9-mediated degradation of the LDLR appears to take place intracellularly and occurs even when endocytosis through clathrin-coated pits is blocked by hypertonic medium.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://www.biomedcentral.com/1471-2121/8/9en
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk molekylærbiologi: 711en
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714en
dc.subject.meshAmmonium Chlorideen
dc.subject.meshCells, Cultureden
dc.subject.meshClathrin-Coated Vesiclesen
dc.subject.meshCulture Media, Conditioneden
dc.subject.meshExtracellular Fluiden
dc.subject.meshHumansen
dc.subject.meshLipoproteins, LDLen
dc.subject.meshMutant Proteinsen
dc.subject.meshNocodazoleen
dc.subject.meshPeptide Hydrolasesen
dc.subject.meshProtein Processing, Post-Translationalen
dc.subject.meshReceptors, LDLen
dc.subject.meshSerine Endopeptidasesen
dc.titleDegradation of the LDL receptors by PCSK9 is not mediated by a secreted protein acted upon by PCSK9 extracellularly.en
dc.typeJournal articleen
dc.typepeer revieweden
dc.contributor.departmentMedical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway. oystein.holla@rikshospitalet.no <oystein.holla@rikshospitalet.no>en
dc.identifier.journalBMC cell biologyen
All Items in HeRA are protected by copyright, with all rights reserved, unless otherwise indicated.