PCSK9 regulates the NODAL signaling pathway and cellular proliferation in hiPSCs

• Published in: Stem cell reports Vol. 16; no. 12; pp. 2958 - 2972
• Main Authors: Roudaut, Meryl, Idriss, Salam, Caillaud, Amandine, Girardeau, Aurore, Rimbert, Antoine, Champon, Benoite, David, Amandine, Lévêque, Antoine, Arnaud, Lucie, Pichelin, Matthieu, Prieur, Xavier, Prat, Annik, Seidah, Nabil G., Zibara, Kazem, Le May, Cedric, Cariou, Bertrand, Si-Tayeb, Karim
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.12.2021; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Cardiology and cardiovascular system; Cell Differentiation; Cell Line; Cell Membrane - metabolism; Cell Proliferation; DACT2; Endocrinology and metabolism; Gene Expression Regulation; hiPSC; Human health and pathology; Humans; Hépatology and Gastroenterology; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Life Sciences; Loss of Function Mutation; NODAL; Nodal Protein - genetics; Nodal Protein - metabolism; PCSK9; Phosphorylation; proliferation; Proprotein Convertase 9 - chemistry; Proprotein Convertase 9 - deficiency; Proprotein Convertase 9 - genetics; Proprotein Convertase 9 - metabolism; Protein Binding; Protein Domains; Receptors, Transforming Growth Factor beta - metabolism; Signal Transduction; SMAD2; Smad2 Protein - metabolism; TGFβR1; Tissues and Organs; Up-Regulation; SMAD2; TGFβR1; proliferation; hiPSC; DACT2; PCSK9; NODAL
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2021.10.004

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) cholesterol metabolism and the target of lipid-lowering drugs. PCSK9 is mainly expressed in hepatocytes. Here, we show that PCSK9 is highly expressed in undifferentiated human induced pluripotent stem cells (hiPSCs). PCSK9 inhibition in hiPSCs with the use of short hairpin RNA (shRNA), CRISPR/cas9-mediated knockout, or endogenous PCSK9 loss-of-function mutation R104C/V114A unveiled its new role as a potential cell cycle regulator through the NODAL signaling pathway. In fact, PCSK9 inhibition leads to a decrease of SMAD2 phosphorylation and hiPSCs proliferation. Conversely, PCSK9 overexpression stimulates hiPSCs proliferation. PCSK9 can interfere with the NODAL pathway by regulating the expression of its endogenous inhibitor DACT2, which is involved in transforming growth factor (TGF) β-R1 lysosomal degradation. Using different PCSK9 constructs, we show that PCSK9 interacts with DACT2 through its Cys-His-rich domain (CHRD) domain. Altogether these data highlight a new role of PCSK9 in cellular proliferation and development. •PCSK9 is highly expressed in undifferentiated hiPSCs•PCSK9 regulates hiPSC proliferation•PCSK9 controls NODAL signaling and SMAD2 phosphorylation in hiPSCs•PCSK9 controls TGFβ-R1 expression, potentially through its interaction with DACT2 In this article, Si-Tayeb and colleagues described that proprotein convertase PCSK9 controls the NODAL signaling pathway through a regulation of SMAD2 phosphorylation in hiPSCs. The endogenous inhibitor of the type 1 TGFβ receptor DACT2 was found as a potential target for PCSK9. These results highlight a new role for PCSK9 in cell proliferation and development.