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Molecules 2012, 17(10), 12086-12101; doi:10.3390/molecules171012086
Article

c-IAP1 Binds and Processes PCSK9 Protein: Linking the c-IAP1 in a TNF-α Pathway to PCSK9-Mediated LDLR Degradation Pathway

†,* ,
 and
The Krebs Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK Current address: London Biotech Ltd, 19 Crawley Road, London, N22 6AN, UK.
* Author to whom correspondence should be addressed.
Received: 17 August 2012 / Revised: 8 October 2012 / Accepted: 9 October 2012 / Published: 15 October 2012
(This article belongs to the Section Molecular Diversity)
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Abstract

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.
Keywords:  c-IAP1; PCSK9; TNF-α; LDLR; Cholesterol;K27; ubiquitination; E3 ligase; Stub1  c-IAP1; PCSK9; TNF-α; LDLR; Cholesterol; K27; ubiquitination; E3 ligase; Stub1
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Xu, W.; Liu, L.; Hornby, D. c-IAP1 Binds and Processes PCSK9 Protein: Linking the c-IAP1 in a TNF-α Pathway to PCSK9-Mediated LDLR Degradation Pathway. Molecules 2012, 17, 12086-12101.

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