The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer
| Autor: | Nabil G. Seidah |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
CHRD
Cys-His-rich domain Apolipoprotein B HEK293 human embryonic kidney 293 DENV dengue virus Familial hypercholesterolemia 030204 cardiovascular system & hematology S1P site 1 protease Biochemistry 0302 clinical medicine Endocrinology Thematic Review Series: The Science of FH Neoplasms lipid metabolism GOF gain-of-function cancer/metastasis Receptor 0303 health sciences biology LDLR LDL receptor SKI-1 subtilisin-kexin isozyme 1 3. Good health Virus Diseases lipids (amino acids peptides and proteins) Proprotein Convertase 9 furin Endosome Hypercholesterolemia QD415-436 FH familial hypercholesterolemia ER endoplasmic reticulum 03 medical and health sciences cDNA complementary DNA lysosomes Zymogen medicine MHC major histocompatibility complex Animals Humans mAb monoclonal antibody LDL-C 030304 developmental biology PCSK9 proprotein convertases Thematic Review Series PC proprotein convertase Cell Biology Proprotein convertase medicine.disease LDLR inflammation LDL receptor Cancer research biology.protein viral infection PCSK9 proprotein convertase subtilisin/kexin type 9 LOF loss of function NARC-1 neural apoptosis-regulated convertase 1 |
| Zdroj: | Journal of Lipid Research Journal of Lipid Research, Vol 62, Iss, Pp 100130-(2021) |
| ISSN: | 1539-7262 0022-2275 |
| Popis: | In 2003 the sequences of mammalian PCSK9 were reported. Radiolabeling pulse-chase analyses demonstrated that PCSK9 was synthesized as a zymogen (proPCSK9) that undergoes autocatalytic cleavage in the endoplasmic reticulum. Distinct from the other proprotein convertases, PCSK9 is 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 3rd locus associated with familial hypercholesterolemia (FH), prompted us to screen a cohort of FH patients with no variations in the LDLR and APOB, two other FH-associated loci, whereupon three patient families expressing the PCSK9 variants S127R or F216L were identified. Although Pcsk9 and Ldlr were downregulated in mice fed a cholesterol-rich diet, PCSK9 overexpression led to the degradation of the low-density lipoprotein receptor (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 non-enzymatic fashion to induce its degradation in endosomes/lysosomes. PCSK9 was also shown to play major roles in targeting other receptors for degradation, thereby regulating processes including hypercholesterolemia and associated atherosclerosis, vascular inflammation, viral infections, and immune checkpoint regulation in cancer. Injectable PCSK9 mAb or siRNA are currently used in clinics worldwide to treat hypercholesterolemia and could be combined with current therapies in cancer/metastasis. In this review, we discuss the critical information leading to the discovery of PCSK9 and its functional mechanism in the regulation of LDL cholesterol, as well as its evolving novel functions in both health and disease states. |
| Databáze: | OpenAIRE |
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