Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects gene expression pathways beyond cholesterol metabolism in liver cells

Hong, Lan; Pang, Lei; Smith, Marsha M.; Levitan, Diane; Ding, Wei; Liu, Li; Shan, Lianwei; Shah, Vidhi V.; Laverty, Maureen; Arreaza, Gladys; Zhang, Qing; Murgolo, Nicholas; Hernandez, Marco; Greene, Jonathan; Gustafson, Eric L.; Bayne, Marvin L.; Davis, Harry R.; Hedrick, Joseph A.

doi:10.1002/jcp.22130

Cited by 69 publications

(48 citation statements)

References 20 publications

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“…Regarding other biological functions, genomewide expression analysis studies predict that PCSK9 could be involved in the down-regulation of stress-response genes and specific inflammatory cytokine pathways [16,17]. Additionally, an in vitro study shows that PCSK9 can reduce the levels of the epithelium sodium channel and so modulate the epithelial sodium absorption, thereby PCSK9 may have a role controlling blood pressure [18].…”

mentioning

confidence: 96%

RNA therapeutics inactivate PCSK9 by inducing a unique intracellular retention form

Rocha

Wiklander

Larsson

et al. 2015

Journal of Molecular and Cellular Cardiology

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Hypercholesterolemia is a medical condition often characterized by high levels of low-density lipoprotein cholesterol (LDL-C) in the blood. Despite the available therapies, not all patients show sufficient responses, especially those with very high levels of LDL-C or those with familial hypercholesterolemia. Regulation of plasma cholesterol levels is very complex and several proteins are involved (both receptors and enzymes). From these, the proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising pharmacologic target. The objective of this work is to develop a new approach to inactivate PCSK9 by splice-switching oligonucleotides (SSOs), converting the normal splice form to a natural, less abundant and inactive, splice variant. For this purpose, a new RNA therapeutic approach for hypercholesterolemia based on SSOs was developed for modulation of the splice pattern of human PCSK9 pre-mRNA. Our results show an increase of the selected splice form at both the mRNA and protein level when compared to non-treated Huh7 and HepG2 cell lines, with concomitant increase of the protein level of the low-density lipoprotein receptor (LDLR) demonstrating the specificity and efficiency of the system. In vivo, full conversion to the splice form was achieved in a reporter system when mice were treated with the specific oligonucleotide, thus further indicating the therapeutic potential of the approach. In conclusion, PCSK9 activity can be modulated by splice-switching through an RNA therapeutic approach. The tuning of the natural active to non-active isoforms represents a physiological way of regulating the cholesterol metabolism, by controlling the amount of LDL receptor available and the rate of LDL-cholesterol clearance.

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mentioning

confidence: 96%

RNA therapeutics inactivate PCSK9 by inducing a unique intracellular retention form

Rocha

Wiklander

Larsson

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…PCSK9 is also involved in numerous biological processes. Microarray studies showed that overexpression of PCSK9 leads to the dysregulation of numerous pathways, including those regulating the cell cycle, apoptosis and inflammation (13,14). In vivo studies also suggested that PCSK9 is implicated in these processes (15,16).…”

Section: Introductionmentioning

confidence: 99%

PCSK9 regulates apoptosis in human lung adenocarcinoma A549 cells via endoplasmic reticulum stress and mitochondrial signaling pathways

Cui

Cao

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the subtilisin family of PCs that encodes a neural apoptosis-regulated convertase 1. However, the precise role of PCSK9 in lung cancer cell apoptosis has remained elusive. In the present study, A549 human lung adenocarcinoma cells were transfected with PCSK9 small interfering (si)RNA to investigate the underlying mechanisms of apoptosis. The results indicated that PCSK9 siRNA exhibited anti-tumor activity by inducing apoptosis as determined by a Cell Counting Kit-8 and Hoechst staining analysis. In addition, PCSK9 siRNA significantly increased apoptosis of A549 cells in part via activation of caspase-3 and downregulation of the anti-apoptotic proteins survivin and X-linked inhibitor of apoptosis protein. Moreover, the results demonstrated that perturbations in the mitochondrial membrane were associated with the deregulation of the Bax/Bcl-2 ratio, which led to the release of cytochrome c after PCSK9 siRNA transfection. In addition, PCSK9 siRNA also induced endoplasmic reticulum stress (ERS) by increasing the levels of 78 kDa glucose-regulated protein (GRP78), GRP94, phosphorylated protein kinase R-like ER kinase and phosphorylated eukaryotic initiation factor 2α. Therefore, these results demonstrated that PCSK9 siRNA may exert its anti-tumor activity through inducing mitochondrial dysfunction and ERS-associated cell death in A549 cells.

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“…The list includes cell-surface proteins as well as intracellular proteins, proteins involved in folding and post-translational modification in the early secretory pathway, proteins involved in vesicle and organelle transport, cytoskeleton as well as cell-adhesion proteins. This global impact of PCSK9/NARC-1 was also demonstrated by two microarrays studies, which implicated this serine protease in many biological pathways [63, 64]. …”

Section: A Novel Form Of Post-translational Regulation In the Ermentioning

confidence: 66%

Lysine acetylation in the lumen of the ER: A novel and essential function under the control of the UPR

Pehar

Puglielli

2013

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The Nε-amino group of lysine residues can be transiently modified by the addition of an acetyl group. Recognized functions of Nε-lysine acetylation include regulation of activity, molecular stabilization and conformational assembly of a protein. For more than forty years lysine acetylation was thought to occur only in the cytosol and nucleus. Targets included cytoskeletal-associated proteins as well as transcription factors, histone proteins and proteins involved in DNA recombination and repair. However, in 2007 we reported that a type I membrane protein involved in the pathogenesis of Alzheimer’s disease was transiently acetylated on the ε amino group of seven lysine residues while transiting along the secretory pathway. Surprisingly, the acetylation occurred in the lumen of the endoplasmic reticulum (ER) forcing us to reconsider old paradigms. Indeed, if lysine acetylation can occur in the lumen of the ER, then all the essential biochemical elements of the reaction must be available in the lumen of the organelle. Follow-up studies revealed the existence of ER-based acetyl-CoA:lysine acetyltransferases as well as a membrane transporter that translocates acetyl-CoA from the cytosol into the ER lumen. Large-scale proteomics showed that the list of substrates of the ER-based acetylation machinery includes both transiting and resident proteins. Finally, genetic studies revealed that this machinery is tightly linked to human diseases. Here, we describe these exciting findings as well as recent biochemical and cellular advances, and discuss possible impact on both human physiology and pathology.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects gene expression pathways beyond cholesterol metabolism in liver cells

Cited by 69 publications

References 20 publications

RNA therapeutics inactivate PCSK9 by inducing a unique intracellular retention form

RNA therapeutics inactivate PCSK9 by inducing a unique intracellular retention form

PCSK9 regulates apoptosis in human lung adenocarcinoma A549 cells via endoplasmic reticulum stress and mitochondrial signaling pathways

Lysine acetylation in the lumen of the ER: A novel and essential function under the control of the UPR

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