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Neuroplastin Modulates Anti-Inflammatory Effects of MANF
37 Pages Posted: 19 May 2020 Publication Status: Published
More...Abstract
Endoplasmic reticulum (ER) stress plays a crucial role in the pathogenesis of various common diseases, such as diabetes mellitus and neurodegenerative disorders, as well as rare inherited diseases including Wolfram syndrome. ER stress is known to induce pro-inflammatory response and ultimately leads to apoptotic cell death. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER-localized protein whose expression and secretion is induced by ER stress, which in turn alleviates ER stress and inflammation. Although multiple studies have shown its therapeutic values in treatments of ER stress-related diseases, the underlying mechanism how MANF exerts its cytoprotective activity remains unclear due to the lack of knowledge of its receptor. Here we show that MANT binds to Neuroplastin (NPTN) on cell surface and mediates MANF-mediated suppression of inflammation. Biochemical analysis shows the physiological interaction between MANF and NPTN on the cell surface. The affinity of MANF to NPTN is higher than that of other related neurotrophic factors, including BDNF and GDNF. Overexpression and knockdown experiments show that NPTN induces inflammation through regulation of the NF-kB signaling pathways. MANF mitigates the inflammatory response and apoptosis mediated by cytokine stimulation or ER stress, and the effects of MANF are abrogated in NPTN deficient cells. Collectively, our results demonstrate that NPTN is a novel cell surface regulator for MANF which modulates inflammatory responses and cell death.
Keywords: MANF, Neuroplastin, ER stress, apoptosis, Inflammation, NF-kB, Wolfram syndrome
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