Neuroplastin Modulates Anti-inflammatory Effects of MANF
Takuya Yagi,
Rie Asada,
Kohsuke Kanekura,
Ave Eesmaa,
Maria Lindahl,
Mart Saarma,
Fumihiko Urano
Affiliations
Takuya Yagi
Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA
Rie Asada
Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA
Kohsuke Kanekura
Department of Molecular Pathology, Tokyo Medical University, Tokyo 160-8402, Japan
Ave Eesmaa
Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland
Maria Lindahl
Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland
Mart Saarma
Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland
Fumihiko Urano
Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Corresponding author
Summary: 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.
