Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
Cell Rep. 2023 Feb 28;42(2):112066. doi: 10.1016/j.celrep.2023.112066. Epub 2023 Feb 3.
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in neurons and pancreatic β cells in vitro and in models of neurodegeneration and diabetes in vivo. However, the exact mode of MANF action has remained elusive. Here, we show that MANF directly interacts with the ER transmembrane unfolded protein response (UPR) sensor IRE1α, and we identify the binding interface between MANF and IRE1α. The expression of wild-type MANF, but not its IRE1α binding-deficient mutant, attenuates UPR signaling by decreasing IRE1α oligomerization; phosphorylation; splicing of Xbp1, Atf6, and Txnip levels; and protecting neurons from ER stress-induced death. MANF-IRE1α interaction and not MANF-BiP interaction is crucial for MANF pro-survival activity in neurons in vitro and is required to protect dopamine neurons in an animal model of Parkinson's disease. Our data show IRE1α as an intracellular receptor for MANF and regulator of neuronal survival.
中脑星形胶质细胞衍生的神经营养因子（MANF）是一种内质网（ER）定位蛋白，在体外的神经元和胰腺β细胞以及体内的神经退行性变和糖尿病模型中具有细胞保护作用。然而，MANF 的确切作用模式仍然难以捉摸。在这里，我们表明 MANF 直接与 ER 跨膜未折叠蛋白反应（UPR）传感器 IRE1α相互作用，并且我们确定了 MANF 和 IRE1α 之间的结合界面。野生型 MANF 的表达，但不是其缺乏 IRE1α 结合能力的突变体，通过降低 IRE1α 寡聚化、磷酸化、Xbp1、Atf6 和 Txnip 水平的剪接来减弱 UPR 信号；并保护神经元免受 ER 应激诱导的死亡。MANF-IRE1α 相互作用而不是 MANF-BiP 相互作用对于 MANF 在体外神经元中的促生存活性至关重要，并且对于保护帕金森病动物模型中的多巴胺神经元是必需的。我们的数据表明 IRE1α 是 MANF 的细胞内受体和神经元存活的调节剂。
