2. Academic Validation
  3. MANF regulates neuronal survival and UPR through its ER-located receptor IRE1α

MANF regulates neuronal survival and UPR through its ER-located receptor IRE1α

  • Cell Rep. 2023 Feb 3;42(2):112066. doi: 10.1016/j.celrep.2023.112066.
Vera Kovaleva 1,  Li-Ying Yu 2,  Larisa Ivanova 3,  Olesya Shpironok 2,  Jinhan Nam 4,  Ave Eesmaa 2,  Esa-Pekka Kumpula 2,  Sven Sakson 2,  Urve Toots 5,  Mart Ustav 5,  Juha T Huiskonen 2,  Merja H Voutilainen 4,  Päivi Lindholm 2,  Mati Karelson 3,  Mart Saarma 6
Affiliations

Affiliations

  • 1 Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland. Electronic address: vera.kovaleva@helsinki.fi.
  • 2 Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
  • 3 Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia.
  • 4 Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland.
  • 5 Icosagen Ltd., 61713 Tartu, Estonia.
  • 6 Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland. Electronic address: mart.saarma@helsinki.fi.
PMID: 36739529 DOI: 10.1016/j.celrep.2023.112066
Abstract

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.

Keywords

BiP; CP: Molecular biology; CP: Neuroscience; ER stress; IRE1α; MANF; PD; Parkinson’s disease; UPR; mesencephalic astrocyte-derived neurotrophic factor; neuronal survival; unfolded protein response.

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