MANF regulates neuronal survival and UPR through its ER-located receptor IRE1α
Vera Kovaleva,
Li-Ying Yu,
Larisa Ivanova,
Olesya Shpironok,
Jinhan Nam,
Ave Eesmaa,
Esa-Pekka Kumpula,
Sven Sakson,
Urve Toots,
Mart Ustav,
Juha T. Huiskonen,
Merja H. Voutilainen,
Päivi Lindholm,
Mati Karelson,
Mart Saarma
Affiliations
Vera Kovaleva
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland; Corresponding author
Li-Ying Yu
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
Larisa Ivanova
Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia
Olesya Shpironok
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
Jinhan Nam
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland
Ave Eesmaa
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
Esa-Pekka Kumpula
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
Sven Sakson
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
Urve Toots
Icosagen Ltd., 61713 Tartu, Estonia
Mart Ustav
Icosagen Ltd., 61713 Tartu, Estonia
Juha T. Huiskonen
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
Merja H. Voutilainen
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland
Päivi Lindholm
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
Mati Karelson
Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia
Mart Saarma
Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland; Corresponding author
Summary: 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.
