The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor
Eesmaa, A., Yu, L.-Y., Göös, H., Nõges, K., Kovaleva, V., Hellman, M., Zimmermann, R., Jung, M., Permi, P., Varjosalo, M., Lindholm, P., & Saarma, M. (2021). The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor. Journal of Biological Chemistry, 296, Article 100295. https://doi.org/10.1016/j.jbc.2021.100295
Published inJournal of Biological Chemistry
© 2021 the Authors
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER-stress regulated protein exhibiting cytoprotective properties through a poorly understood mechanism in various in vitro and in vivo models of neuronal and non-neuronal damage. Although initially characterized as a secreted neurotrophic factor for midbrain dopamine neurons, MANF has recently gained more interest for its intracellular role in regulating the ER homeostasis, including serving as a cofactor of the chaperone GRP78. We aimed for a better understanding of the neuroprotective mechanisms of MANF. Here we show for the first time that MANF promotes the survival of ER-stressed neurons in vitro as a general unfolded protein response (UPR) regulator, affecting several UPR pathways simultaneously. Interestingly, MANF does not affect naïve neurons. We hypothesize that MANF regulates UPR signaling towards a mode more compatible with neuronal survival. Screening of MANF interacting proteins from two mammalian cell lines revealed a conserved interactome of 15 proteins including several ER chaperones such as GRP78, GRP170, PDIA1 and PDIA6. Further characterization confirmed previously published finding that MANF is a cofactor of GRP78 interacting with its nucleotide binding domain. Using microscale thermophoresis and NMR spectroscopy, we discovered that MANF is an ATP binding protein and that ATP blocks the MANF-GRP78 interaction. Interestingly, functional analysis of the antiapoptotic properties of MANF mutants in cultured neurons revealed divergent roles of MANF as a GRP78 cofactor and as an antiapoptotic regulator of UPR. We conclude that the co-factor type interaction with GRP78 is dispensable for the survival-promoting activity of MANF in neurons. ...
mesencephalic astrocyte-derived neurotrophic factor (MANF) GRP78 unfolded protein response (UPR) endoplasmic reticulum stress (ER stress) dopamine neurons neuronal cell death protein-protein interaction neuroprotection apoptosis ATP adenosiinitrifosfaatti hermosolut proteiinit ohjelmoitunut solukuolema
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Additional information about fundingThe authors thank Linda Hendershot for GRP170 expression plasmid. This work was funded by Jane and Aatos Erkko Foundation, Academy of Finland (grant 1310891) and European Union H2020 project “TreatER” (No 732386). AE was also supported by the Integrative Life Sciences Doctoral Programme, University of Helsinki. MJ and RZ were supported by grants from the Deutsche Forschungsgemeinschaft (SFB 894).
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