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

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Received: 17 August 2012; in revised form: 8 October 2012 / Accepted: 9 October 2012 / Published: 15 October 2012
(This article belongs to the Section Theoretical Chemistry)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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
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MDPI and ACS Style

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.

AMA Style

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(10):12086-12101.

Chicago/Turabian Style

Xu, Weiming; Liu, Lizhi; Hornby, David. 2012. "c-IAP1 Binds and Processes PCSK9 Protein: Linking the c-IAP1 in a TNF-α Pathway to PCSK9-Mediated LDLR Degradation Pathway." Molecules 17, no. 10: 12086-12101.

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