可欣
前蛋白转化酶
PCSK9
细胞生物学
生物
低密度脂蛋白受体
β细胞
细胞内
胰岛素
胆固醇
脂蛋白
生物化学
内分泌学
小岛
作者
Kevin Saitoski,Maria Ryaboshapkina,Ghaith M Hamza,Andrew F. Jarnuczak,Claire Berthault,Françoise Carlotti,Mathieu Armanet,Kaushik Sengupta,Christina R. Underwood,Shalini Andersson,Isabelle Guillas,Wilfried Le Goff,Raphael Scharfmann
标识
DOI:10.1016/j.jbc.2022.102096
摘要
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in the degradation of the low-density lipoprotein receptor. PCSK9 also targets proteins involved in lipid metabolism (very low-density lipoprotein receptor), immunity (major histocompatibility complex I), and viral infection (cluster of differentiation 81). Recent studies have also indicated that PCSK9 loss-of-function mutations are associated with an increased incidence of diabetes; however, the expression and function of PCSK9 in insulin-producing pancreatic beta cells remain unclear. Here, we studied PCSK9 regulation and function by performing loss- and gain-of-function experiments in the human beta cell line EndoC-βH1. We demonstrate that PCSK9 is expressed and secreted by EndoC-βH1 cells. We also found that PCSK9 expression is regulated by cholesterol and sterol regulatory element-binding protein transcription factors, as previously demonstrated in other cell types such as hepatocytes. Importantly, we show that PCSK9 knockdown using siRNA results in deregulation of various elements of the transcriptome, proteome, and secretome, and increases insulin secretion. We also observed that PCSK9 decreases low-density lipoprotein receptor and very low-density lipoprotein receptor levels via an extracellular signaling mechanism involving exogenous PCSK9, as well as levels of cluster of differentiation 36, a fatty acid transporter, through an intracellular signaling mechanism. Finally, we found that PCSK9 regulates the cell surface expression of PDL1 and HLA-ABC, proteins involved in cell-lymphocyte interaction, also via an intracellular mechanism. Collectively, these results highlight PCSK9 as a regulator of multiple cell surface receptors in pancreatic beta cells.
科研通智能强力驱动
Strongly Powered by AbleSci AI