Department of Medical Cell Biology, Uppsala University, 751 23 Uppsala, Sweden.
Department of Neurobiology, Care Sciences and Society, Division for Neurogeriatrics, Karolinska Institutet, 141 86 Huddinge, Sweden.
Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):E2752-E2761. doi: 10.1073/pnas.1715951115. Epub 2018 Mar 5.
Aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils in islets of Langerhans is associated with type 2 diabetes, and formation of toxic IAPP species is believed to contribute to the loss of insulin-producing beta cells. The BRICHOS domain of integral membrane protein 2B (Bri2), a transmembrane protein expressed in several peripheral tissues and in the brain, has recently been shown to prevent fibril formation and toxicity of Aβ42, an amyloid-forming peptide in Alzheimer disease. In this study, we demonstrate expression of Bri2 in human islets and in the human beta-cell line EndoC-βH1. Bri2 colocalizes with IAPP intracellularly and is present in amyloid deposits in patients with type 2 diabetes. The BRICHOS domain of Bri2 effectively inhibits fibril formation in vitro and instead redirects IAPP into formation of amorphous aggregates. Reduction of endogenous Bri2 in EndoC-βH1 cells with siRNA increases sensitivity to metabolic stress leading to cell death while a concomitant overexpression of Bri2 BRICHOS is protective. Also, coexpression of IAPP and Bri2 BRICHOS in lateral ventral neurons of results in an increased cell survival. IAPP is considered to be the most amyloidogenic peptide known, and described findings identify Bri2, or in particular its BRICHOS domain, as an important potential endogenous inhibitor of IAPP aggregation and toxicity, with the potential to be a possible target for the treatment of type 2 diabetes.
胰岛淀粉样多肽（IAPP）在胰岛中的聚集与 2 型糖尿病有关，而有毒的 IAPP 物种的形成被认为是导致胰岛素产生β细胞丧失的原因。整合膜蛋白 2B（Bri2）的 BRICHOS 结构域是一种跨膜蛋白，在几种外周组织和大脑中表达，最近已被证明可防止淀粉样β肽（Aβ42）的纤维形成和毒性，Aβ42 是阿尔茨海默病中的一种形成淀粉样的肽。在这项研究中，我们证明了 Bri2 在人胰岛和人β细胞系 EndoC-βH1 中的表达。Bri2 与 IAPP 在细胞内共定位，并且存在于 2 型糖尿病患者的淀粉样沉积物中。Bri2 的 BRICHOS 结构域在体外有效地抑制纤维形成，而是将 IAPP 重新定向形成无定形聚集体。用 siRNA 减少 EndoC-βH1 细胞中的内源性 Bri2 会增加对代谢应激的敏感性，导致细胞死亡，而同时过表达 Bri2 BRICHOS 则具有保护作用。此外，IAPP 和 Bri2 BRICHOS 在 lateral ventral 神经元中的共表达会导致细胞存活率增加。IAPP 被认为是已知最具淀粉样特性的肽，描述的发现确定 Bri2 或其 BRICHOS 结构域为 IAPP 聚集和毒性的重要潜在内源性抑制剂，具有成为 2 型糖尿病治疗的可能靶点的潜力。
