The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor

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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 , vol. 296 , 100295 . https://doi.org/10.1016/j.jbc.2021.100295

Title: The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor
Author: Eesmaa, Ave; Yu, Li-Ying; Göös, Helka; Nõges, Kristofer; Kovaleva, Vera; Hellman, Maarit; Zimmermann, Richard; Jung, Martin; Permi, Perttu; Varjosalo, Markku; Lindholm, Paivi; Saarma, Mart
Other contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Molecular Systems Biology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Mart Saarma / Principal Investigator



Date: 2021
Language: eng
Number of pages: 23
Belongs to series: Journal of Biological Chemistry
ISSN: 0021-9258
DOI: https://doi.org/10.1016/j.jbc.2021.100295
URI: http://hdl.handle.net/10138/335440
Abstract: Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (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 glucose-regulated protein 78 (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 naive neurons. We hypothesize that MANF regulates UPR signaling toward 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, protein disulfide isomerase family A member 1, and protein disulfide isomerase family A member 6. Further characterization confirmed previously published finding that MANF is a cofactor of GRP78 interacting with its nucleotide binding domain. Using microscale thermophoresis and nuclear magnetic resonance 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.
Subject: ENDOPLASMIC-RETICULUM STRESS
NEUROTROPHIC FACTOR MANF
ER-STRESS
COMPREHENSIVE RESOURCE
BIP
BINDING
ATF6
ATP
DISSOCIATION
IRE1-ALPHA
1182 Biochemistry, cell and molecular biology
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