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Book: Proprotein convertases

Mbikay, Majambu / Seidah, Nabil G.

(Methods in molecular medicine ; 768 ; Springer protocols)

2011

Author's details	ed. by Majambu Mbikay ; Nabil G. Seidah
Series title	Methods in molecular medicine ; 768 Springer protocols Methods in molecular biology
Collection	Methods in molecular biology
Language	English
Size	XI, 367 S. : Ill., graph. Darst.
Publisher	Humana Press
Publishing place	New York u.a.
Publishing country	United States
Document type	Book
HBZ-ID	HT016829695
ISBN	978-1-61779-203-8 ; 9781617792045 ; 1-61779-203-9 ; 1617792047
Database	Catalogue ZB MED Medicine, Health

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Article ; Online: The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer.

Seidah, Nabil G

Journal of lipid research

2021 Volume 62, Page(s) 100130

Abstract: In 2003, the sequences of mammalian proprotein convertase subtilisin/kexin type 9 (PCSK9) were reported. Radiolabeling pulse-chase analyses demonstrated that PCSK9 was synthesized as a precursor (proPCSK9) that undergoes autocatalytic cleavage in the ... ...

Abstract	In 2003, the sequences of mammalian proprotein convertase subtilisin/kexin type 9 (PCSK9) were reported. Radiolabeling pulse-chase analyses demonstrated that PCSK9 was synthesized as a precursor (proPCSK9) that undergoes autocatalytic cleavage in the endoplasmic reticulum into PCSK9, which is then secreted as an inactive enzyme in complex with its inhibitory prodomain. Its high mRNA expression in liver hepatocytes and its gene localization on chromosome 1p32, a third locus associated with familial hypercholesterolemia, other than LDLR or APOB, led us to identify three patient families expressing the PCSK9 variants S127R or F216L. Although Pcsk9 and Ldlr were downregulated in mice that were fed a cholesterol-rich diet, PCSK9 overexpression led to the degradation of the LDLR. This led to the demonstration that gain-of-function and loss-of-function variations in PCSK9 modulate its bioactivity, whereby PCSK9 binds the LDLR in a nonenzymatic fashion to induce its degradation in endosomes/lysosomes. PCSK9 was also shown to play major roles in targeting other receptors for degradation, thereby regulating various processes, including hypercholesterolemia and associated atherosclerosis, vascular inflammation, viral infections, and immune checkpoint regulation in cancer. Injectable PCSK9 monoclonal antibody or siRNA is currently used in clinics worldwide to treat hypercholesterolemia and could be combined with current therapies in cancer/metastasis. In this review, we present the critical information that led to the discovery of PCSK9 and its implication in LDL-C metabolism. We further analyze the underlying functional mechanism(s) in the regulation of LDL-C, as well as the evolving novel roles of PCSK9 in both health and disease states.
MeSH term(s)	Animals ; Humans ; Hypercholesterolemia/enzymology ; Neoplasms/enzymology ; Proprotein Convertase 9/metabolism ; Virus Diseases/enzymology
Chemical Substances	Proprotein Convertase 9 (EC 3.4.21.-)
Language	English
Publishing date	2021-10-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1016/j.jlr.2021.100130
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Article ; Online: The Elusive Inhibitory Function of the Acidic N-Terminal Segment of the Prodomain of PCSK9: The Plot Thickens.

Seidah, Nabil G

Journal of molecular biology

2019 Volume 431, Issue 5, Page(s) 904–907

MeSH term(s)	Amino Acid Sequence ; Proprotein Convertase 9 ; Serine Endopeptidases
Chemical Substances	PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2019-01-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2019.01.015
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Article ; Online: The Multifaceted Biology of PCSK9.

Seidah, Nabil G / Prat, Annik

Endocrine reviews

2022 Volume 43, Issue 3, Page(s) 558–582

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Biology ; Female ; Humans ; Mice ; Neoplasms/drug therapy ; Proprotein Convertase 9/genetics ; Proprotein Convertase 9/metabolism ; SARS-CoV-2 ; COVID-19 Drug Treatment
Chemical Substances	PCSK9 protein, human (EC 3.4.21.-) ; Pcsk9 protein, mouse (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-)
Language	English
Publishing date	2022-05-18
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	603096-8
ISSN	1945-7189 ; 0163-769X
ISSN (online)	1945-7189
ISSN	0163-769X
DOI	10.1210/endrev/bnab035
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Article ; Online: Expanding Biology of PCSK9: Roles in Atherosclerosis and Beyond.

Seidah, Nabil G / Garçon, Damien

Current atherosclerosis reports

2022 Volume 24, Issue 10, Page(s) 821–830

Abstract: Purpose of review: Since the discovery of PCSK9 in 2003, this proprotein convertase was shown to target specific receptors for degradation in endosomes/lysosomes, including LDLR and other family members and hence to enhance the levels of circulating LDL- ...

Abstract	Purpose of review: Since the discovery of PCSK9 in 2003, this proprotein convertase was shown to target specific receptors for degradation in endosomes/lysosomes, including LDLR and other family members and hence to enhance the levels of circulating LDL-cholesterol (LDLc). Accordingly, inhibitors of PCSK9, including monoclonal antibodies blocking its circulating activity and siRNA silencers of its hepatic expression, are now used in clinics worldwide to treat hypercholesterolemia patients effectively and safely in combination with statins and/or ezetimibe. These powerful treatments reduce the incidence of atherosclerosis by at least 20%. Since 2008, novel targets of PCSK9 began to be defined, thereby expanding its roles beyond LDLc regulation into the realm of inflammation, pathogen infections and cellular proliferation in various cancers and associated metastases. Recent findings: Some pathogens such as dengue virus exploit the ability of PCSK9 to target the LDLR for degradation to enhance their ability to infect cells. Aside from increasing the degradation of the LDLR and its family members VLDLR, ApoER2 and LRP1, circulating PCSK9 also reduces the levels of other receptors such as CD36 (implicated in fatty acid uptake), oxidized LDLR receptor (that clears oxidized LDLc) as well as major histocompatibility class-I (MHC-I) receptors (implicated in the immune response to antigens). Thus, these novel targets provided links between PCSK9 and inflammation/atherosclerosis, viral infections and cancer/metastasis. The functional activities of PCSK9, accelerated the development of novel therapies to inhibit PCSK9 functions, including small molecular inhibitors, long-term vaccines, and possibly CRISPR-based silencing of hepatic expression of PCSK9. The future of inhibitors/silencers of PCSK9 function or expression looks bright, as these are expected to provide a modern armamentarium to treat various pathologies beyond hypercholesterolemia and its effects on atherosclerosis.
MeSH term(s)	Atherosclerosis ; Cholesterol, LDL/metabolism ; Humans ; Hypercholesterolemia/therapy ; Inflammation ; Proprotein Convertase 9/physiology ; Receptors, LDL/metabolism
Chemical Substances	Cholesterol, LDL ; Receptors, LDL ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-)
Language	English
Publishing date	2022-07-29
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2057369-8
ISSN	1534-6242 ; 1523-3804
ISSN (online)	1534-6242
ISSN	1523-3804
DOI	10.1007/s11883-022-01057-z
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Article: The PCSK9 revolution and the potential of PCSK9-based therapies to reduce LDL-cholesterol.

Seidah, Nabil G

Global cardiology science & practice

2017 Volume 2017, Issue 1, Page(s) e201702

Language	English
Publishing date	2017-03-31
Publishing country	Qatar
Document type	Journal Article ; Review
ZDB-ID	2738381-7
ISSN	2305-7823
ISSN	2305-7823
DOI	10.21542/gcsp.2017.2
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Article: Post-Transcriptional Effects of miRNAs on PCSK7 Expression and Function: miR-125a-5p, miR-143-3p, and miR-409-3p as Negative Regulators.

Malakootian, Mahshid / Naeli, Parisa / Mowla, Seyed Javad / Seidah, Nabil G

Metabolites

2022 Volume 12, Issue 7

Abstract: The regulatory mechanism ... ...

Abstract	The regulatory mechanism of
Language	English
Publishing date	2022-06-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo12070588
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Article ; Online: PCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity.

Alannan, Malak / Seidah, Nabil G / Merched, Aksam J

Cells

2022 Volume 11, Issue 24

Abstract: Metabolic rewiring and defective immune responses are considered to be the main driving forces sustaining cell growth and oncogenesis in many cancers. The atypical enzyme, proprotein convertase subtilisin/kexin type 9 (PCSK9), is produced by the liver in ...

Abstract	Metabolic rewiring and defective immune responses are considered to be the main driving forces sustaining cell growth and oncogenesis in many cancers. The atypical enzyme, proprotein convertase subtilisin/kexin type 9 (PCSK9), is produced by the liver in large amounts and plays a major role in lipid metabolism via the control of the low density lipoprotein receptor (LDLR) and other cell surface receptors. In this context, many clinical studies have clearly demonstrated the high efficacy of PCSK9 inhibitors in treating hyperlipidemia and cardiovascular diseases. Recent data implicated PCSK9 in the degradation of major histocompatibility complex I (MHC-I) receptors and the immune system as well as in other physiological activities. This review highlights the complex crosstalk between PCSK9, lipid metabolism and immunosuppression and underlines the latest advances in understanding the involvement of this convertase in other critical functions. We present a comprehensive assessment of the different strategies targeting PCSK9 and show how these approaches could be extended to future therapeutic options to treat cancers with a main focus on the liver.
MeSH term(s)	Humans ; Proprotein Convertase 9/metabolism ; Lipid Metabolism ; Hyperlipidemias ; Liver Neoplasms
Chemical Substances	PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-)
Language	English
Publishing date	2022-12-19
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11244132
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Article ; Online: Insights into a PCSK9 structural groove: a harbinger of new drugs to reduce LDL-cholesterol.

Seidah, Nabil G

Nature structural & molecular biology

2017 Volume 24, Issue 10, Page(s) 785–786

MeSH term(s)	Animals ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/pharmacology ; Anticholesteremic Agents/chemistry ; Anticholesteremic Agents/pharmacology ; Biological Transport/drug effects ; Cholesterol, LDL/antagonists & inhibitors ; Cholesterol, LDL/metabolism ; Endosomes/drug effects ; Endosomes/metabolism ; Hepatocytes/cytology ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Humans ; Hypercholesterolemia/drug therapy ; Hypercholesterolemia/genetics ; Hypercholesterolemia/metabolism ; Hypercholesterolemia/pathology ; Liver/drug effects ; Liver/metabolism ; Lysosomes/drug effects ; Lysosomes/metabolism ; Mice ; Proprotein Convertase 9/antagonists & inhibitors ; Proprotein Convertase 9/chemistry ; Proprotein Convertase 9/genetics ; Proprotein Convertase 9/metabolism ; Proteolysis/drug effects ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Receptors, LDL/genetics ; Receptors, LDL/metabolism
Chemical Substances	Antibodies, Monoclonal ; Anticholesteremic Agents ; Cholesterol, LDL ; LDLR protein, human ; RNA, Small Interfering ; Receptors, LDL ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; evolocumab (LKC0U3A8NJ)
Language	English
Publishing date	2017-11-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/nsmb.3471
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Article ; Online: New developments in proprotein convertase subtilisin-kexin 9's biology and clinical implications.

Seidah, Nabil G

Current opinion in lipidology

2016 Volume 27, Issue 3, Page(s) 274–281

Abstract: Purpose of review: High levels of LDL-cholesterol (LDL-C) are directly associated with devastating cardiovascular complications. Statins downregulate cholesterol synthesis and upregulate hepatic mRNA levels of LDL receptor (LDLR) and proprotein ... ...

Abstract	Purpose of review: High levels of LDL-cholesterol (LDL-C) are directly associated with devastating cardiovascular complications. Statins downregulate cholesterol synthesis and upregulate hepatic mRNA levels of LDL receptor (LDLR) and proprotein convertase subtilisin-kexin 9 (PCSK9), a validated enhancer of LDLR protein degradation. Herein, we summarize recent discoveries of the biological properties of PCSK9 in both health and disease states. Recent findings: PCSK9 downregulation of the LDLR protein likely explains the observed protective effect of the loss of PCSK9 in reducing lipoprotein(a) and incidence of septic shock. Injectable inhibitory PCSK9 monoclonal antibodies are now prescribed to hypercholesterolemic patients that do not reach target levels of LDL-C with available drugs. PCSK9 also reduces the levels of other receptors, for example, VLDL receptor (VLDLR), ApoER2, CD36, and CD81. The efficacy of the upregulation of LDLR and VLDLR cell surface levels in the absence of PCSK9 is both tissue and sex dependent. As LDLR, CD81, and VLDLR are hepatitis C receptors, PCSK9 may protect against certain viral infections. Summary: New functions of PCSK9 and other receptor targets are beginning to emerge to explain the observed changes in LDL-C and triglycerides. The effect of PCSK9 loss-of-function on glucose metabolism, factors that regulate the expression of PCSK9, and the roles of PCSK9 in other tissues, for example, intestine, kidney, and brain require further investigations.
MeSH term(s)	Cholesterol, LDL/metabolism ; Disease ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Proprotein Convertase 9/metabolism ; Receptors, LDL/metabolism ; Triglycerides/metabolism
Chemical Substances	Cholesterol, LDL ; Receptors, LDL ; Triglycerides ; Proprotein Convertase 9 (EC 3.4.21.-)
Language	English
Publishing date	2016
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1045394-5
ISSN	1473-6535 ; 0957-9672
ISSN (online)	1473-6535
ISSN	0957-9672
DOI	10.1097/MOL.0000000000000295
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