Yagi Takuya, Asada Rie, Kanekura Kohsuke, Eesmaa Ave, Lindahl Maria, Saarma Mart, Urano Fumihiko
Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Molecular Pathology, Tokyo Medical University, Tokyo 160-8402, Japan.
iScience. 2020 Nov 17;23(12):101810. doi: 10.1016/j.isci.2020.101810. eCollection 2020 Dec 18.
Endoplasmic reticulum (ER) stress is known to induce pro-inflammatory response and ultimately leads to cell death. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER-localized protein whose expression and secretion is induced by ER stress and a crucial survival factor. However, the underlying mechanism of how MANF exerts its cytoprotective activity remains unclear due to the lack of knowledge of its receptor. Here we show that Neuroplastin (NPTN) is such a receptor for MANF. Biochemical analysis shows the physiological interaction between MANF and NPTN on the cell surface. Binding of MANF to NPTN mitigates the inflammatory response and apoptosis via suppression of NF-kβ signaling. Our results demonstrate that NPTN is a cell surface receptor for MANF, which modulates inflammatory responses and cell death, and that the MANF-NPTN survival signaling described here provides potential therapeutic targets for the treatment of ER stress-related disorders, including diabetes mellitus, neurodegeneration, retinal degeneration, and Wolfram syndrome.
已知内质网（ER）应激会诱导促炎反应并最终导致细胞死亡。中脑星形胶质细胞衍生的神经营养因子（MANF）是一种定位于内质网的蛋白质，其表达和分泌由内质网应激诱导，是一种关键的生存因子。然而，由于缺乏对其受体的了解，MANF发挥其细胞保护活性的潜在机制仍不清楚。在这里，我们表明神经塑蛋白（NPTN）就是MANF的这样一种受体。生化分析显示了MANF与NPTN在细胞表面的生理相互作用。MANF与NPTN的结合通过抑制NF-κβ信号传导减轻炎症反应和细胞凋亡。我们的结果表明，NPTN是MANF的细胞表面受体，可调节炎症反应和细胞死亡，并且这里描述的MANF-NPTN生存信号为治疗内质网应激相关疾病提供了潜在的治疗靶点，这些疾病包括糖尿病、神经退行性变、视网膜变性和沃夫勒姆综合征。
