c-IAP1 Binds and Processes PCSK9 Protein: Linking the c-IAP1 in a TNF-α Pathway to PCSK9-Mediated LDLR Degradation Pathway
| Autor: | David P. Hornby, Lizhi Liu, Weiming Xu |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Proteomics
K27 Pharmaceutical Science Plasma protein binding Biology ubiquitination Stub1 Article Cell Line Inhibitor of Apoptosis Proteins c-IAP1 Analytical Chemistry PCSK9 lcsh:QD241-441 Mice PCSK9 Gene lcsh:Organic chemistry Ubiquitin Protein Interaction Mapping Drug Discovery Animals Humans Physical and Theoretical Chemistry E3 ligase STUB1 Gene knockdown Tumor Necrosis Factor-alpha Serine Endopeptidases Organic Chemistry Molecular biology Ubiquitin ligase LDLR Cholesterol Receptors LDL Chemistry (miscellaneous) Gene Knockdown Techniques TNF-α Proteolysis LDL receptor biology.protein Molecular Medicine Proprotein Convertases Proprotein Convertase 9 Signal transduction Carrier Proteins Protein Binding Signal Transduction |
| Zdroj: | Molecules, Vol 17, Iss 10, Pp 12086-12101 (2012) Molecules Volume 17 Issue 10 Pages 12086-12101 |
| ISSN: | 1420-3049 |
| Popis: | Recent genetic studies have shown that PCSK9, one of the key genes in cholesterol metabolism, plays a critical role by controlling the level of low-density lipoprotein receptor. However, how PCSK9 mediates LDLR degradation is still unknown. By combining a shotgun proteomic method and differential analysis of natural occurring mutations of the PCSK9 gene, we found that an E3 ubiquitin ligase c-IAP1 binds and processes PCSK9 protein. One of the ‘gain-of-function’ mutations, S127R, is defective with respect to binding to c-IAP1, and thus has defective autocatalytic activity. Knockdown of c-IAP1 impairs PCSK9 processing and autocatalytic cleavage. In c-IAP1 null mouse embryonic fibroblasts (MEFs), there is a dramatic decrease in secreted mature PCSK9 protein accompanied by a significant increase in LDLR protein levels compared with matched wild-type MEF cells. c-IAP1 also acts as an E3 ligase for ubiquitination of PCSK9. Ubiquitin containing only lysine-27 mediated PCSK9 ubiquitination by c-IAP1. Given K27-linked polyubiquitination promotes lysosomal localization, the finding indicates the c-IAP1 acts on both secretion of PCSK9 and its lysosomal localization. The novel pathway described here will open new avenues for exploring novel disease treatments. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|