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MANF regulates unfolded protein response and neuronal survival through its ER-located receptor IRE1α

View ORCID ProfileVera Kovaleva, View ORCID ProfileLi-Ying Yu, View ORCID ProfileLarisa Ivanova, View ORCID ProfileJinhan Nam, View ORCID ProfileAve Eesmaa, View ORCID ProfileEsa-Pekka Kumpula, View ORCID ProfileJuha Huiskonen, View ORCID ProfilePäivi Lindholm, View ORCID ProfileMerja Voutilainen, View ORCID ProfileMati Karelson, View ORCID ProfileMart Saarma
doi: https://doi.org/10.1101/2020.09.22.307744
Vera Kovaleva
1Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
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  • For correspondence: vera.kovaleva@helsinki.fi
Li-Ying Yu
1Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
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Larisa Ivanova
2Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia
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  • ORCID record for Larisa Ivanova
Jinhan Nam
1Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
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Ave Eesmaa
1Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
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Esa-Pekka Kumpula
1Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
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Juha Huiskonen
1Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
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Päivi Lindholm
1Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
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Merja Voutilainen
1Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
3Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland
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Mati Karelson
2Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia
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Mart Saarma
1Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
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Abstract

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in numerous cell types in vitro and in models of neurodegeneration and diabetes in vivo. So far, the exact mode of its action has remained elusive and plasma membrane or ER-located receptors of MANF have not been identified. We have found that MANF can directly interact with transmembrane unfolded protein response (UPR) receptor IRE1α and compete with the major ER chaperone BiP (GRP78) for the interaction with IRE1α. With lower affinities MANF can also interact with other UPR receptors, PERK and ATF6. Using molecular modeling and mutagenesis analysis, we have identified the exact structural MANF regions involved in its binding to the luminal domain of IRE1α. MANF attenuates UPR signaling by decreasing IRE1α oligomerization and IRE1α phosphorylation. MANF mutant deficient in IRE1α binding cannot regulate IRE1α oligomerization and fails to protect neurons from ER stress induced death. Importantly, we found that MANF-IRE1α interaction is also crucial for the survival promoting action of MANF for dopamine neurons in an animal model of Parkinson’s disease. Our data reveal a novel mechanism of IRE1α regulation during ER stress and demonstrate the intracellular mode of action of MANF as a modulator of UPR and neuronal cell survival through the direct interaction with IRE1α and regulation of its activity. Furthermore, our data explain why MANF in contrast to other growth factors has no effects on naive cells and rescues only ER stressed or injured cells.

Competing Interest Statement

The authors have declared no competing interest.

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Posted September 22, 2020.
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MANF regulates unfolded protein response and neuronal survival through its ER-located receptor IRE1α
Vera Kovaleva, Li-Ying Yu, Larisa Ivanova, Jinhan Nam, Ave Eesmaa, Esa-Pekka Kumpula, Juha Huiskonen, Päivi Lindholm, Merja Voutilainen, Mati Karelson, Mart Saarma
bioRxiv 2020.09.22.307744; doi: https://doi.org/10.1101/2020.09.22.307744
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MANF regulates unfolded protein response and neuronal survival through its ER-located receptor IRE1α
Vera Kovaleva, Li-Ying Yu, Larisa Ivanova, Jinhan Nam, Ave Eesmaa, Esa-Pekka Kumpula, Juha Huiskonen, Päivi Lindholm, Merja Voutilainen, Mati Karelson, Mart Saarma
bioRxiv 2020.09.22.307744; doi: https://doi.org/10.1101/2020.09.22.307744

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