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The Multifaceted Biology of PCSK9

This article reviews the discovery of PCSK9, its structure–function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the...

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Autores principales: Seidah, Nabil G, Prat, Annik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113161/
https://www.ncbi.nlm.nih.gov/pubmed/35552680
http://dx.doi.org/10.1210/endrev/bnab035
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author Seidah, Nabil G
Prat, Annik
author_facet Seidah, Nabil G
Prat, Annik
author_sort Seidah, Nabil G
collection PubMed
description This article reviews the discovery of PCSK9, its structure–function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the levels of circulating low-density lipoprotein (LDL)-cholesterol (LDLc), via its ability to enhance the sorting and escort of the cell surface LDL receptor (LDLR) to lysosomes. This implicates the binding of the catalytic domain of PCSK9 to the EGF-A domain of the LDLR. This also requires the presence of the C-terminal Cys/His-rich domain, its binding to the secreted cytosolic cyclase associated protein 1, and possibly another membrane-bound “protein X”. Curiously, in PCSK9-deficient mice, an alternative to the downregulation of the surface levels of the LDLR by PCSK9 is taking place in the liver of female mice in a 17β-estradiol-dependent manner by still an unknown mechanism. Recent studies have extended our understanding of the biological functions of PCSK9, namely its implication in septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation in cancer via the regulation of the cell surface levels of the T-cell receptor and MHC-I, which govern the antitumoral activity of CD8(+) T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors that reduces by 50% to 60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 monoclonal antibody or small interfering RNA could be added to current immunotherapies in cancer/metastasis.
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spelling pubmed-91131612022-05-18 The Multifaceted Biology of PCSK9 Seidah, Nabil G Prat, Annik Endocr Rev Review This article reviews the discovery of PCSK9, its structure–function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the levels of circulating low-density lipoprotein (LDL)-cholesterol (LDLc), via its ability to enhance the sorting and escort of the cell surface LDL receptor (LDLR) to lysosomes. This implicates the binding of the catalytic domain of PCSK9 to the EGF-A domain of the LDLR. This also requires the presence of the C-terminal Cys/His-rich domain, its binding to the secreted cytosolic cyclase associated protein 1, and possibly another membrane-bound “protein X”. Curiously, in PCSK9-deficient mice, an alternative to the downregulation of the surface levels of the LDLR by PCSK9 is taking place in the liver of female mice in a 17β-estradiol-dependent manner by still an unknown mechanism. Recent studies have extended our understanding of the biological functions of PCSK9, namely its implication in septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation in cancer via the regulation of the cell surface levels of the T-cell receptor and MHC-I, which govern the antitumoral activity of CD8(+) T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors that reduces by 50% to 60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 monoclonal antibody or small interfering RNA could be added to current immunotherapies in cancer/metastasis. Oxford University Press 2021-10-09 /pmc/articles/PMC9113161/ /pubmed/35552680 http://dx.doi.org/10.1210/endrev/bnab035 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Review
Seidah, Nabil G
Prat, Annik
The Multifaceted Biology of PCSK9
title The Multifaceted Biology of PCSK9
title_full The Multifaceted Biology of PCSK9
title_fullStr The Multifaceted Biology of PCSK9
title_full_unstemmed The Multifaceted Biology of PCSK9
title_short The Multifaceted Biology of PCSK9
title_sort multifaceted biology of pcsk9
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113161/
https://www.ncbi.nlm.nih.gov/pubmed/35552680
http://dx.doi.org/10.1210/endrev/bnab035
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