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

Show simple item record 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 2021-10-19T07:57:02Z 2021-10-19T07:57:02Z 2021
dc.identifier.citation 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 .
dc.identifier.other PURE: 169270001
dc.identifier.other PURE UUID: ea4b6708-8220-4b58-a2ba-ea4c8c740cf5
dc.identifier.other WOS: 000672866400269
dc.identifier.other ORCID: /0000-0003-3022-5035/work/101724452
dc.identifier.other ORCID: /0000-0002-1340-9732/work/101725040
dc.identifier.other ORCID: /0000-0002-6175-4872/work/101725797
dc.identifier.other ORCID: /0000-0001-5543-7160/work/101727176
dc.description.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. en
dc.format.extent 23
dc.language.iso eng
dc.relation.ispartof Journal of Biological Chemistry
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject ER-STRESS
dc.subject BIP
dc.subject BINDING
dc.subject ATF6
dc.subject ATP
dc.subject IRE1-ALPHA
dc.subject 1182 Biochemistry, cell and molecular biology
dc.title The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor en
dc.type Article
dc.contributor.organization Institute of Biotechnology
dc.contributor.organization Molecular Systems Biology
dc.contributor.organization Biosciences
dc.contributor.organization Mart Saarma / Principal Investigator
dc.description.reviewstatus Peer reviewed
dc.relation.issn 0021-9258
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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