Affinage

MANF

Mesencephalic astrocyte-derived neurotrophic factor · UniProt P55145

Length
182 aa
Mass
20.7 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MANF is a bifunctional ER-resident and secreted protein that maintains endoplasmic reticulum proteostasis and confers cytoprotection across neuronal, pancreatic, hepatic, immune, and cardiac tissues, functioning as a secreted mediator of the adaptive unfolded protein response (UPR) (PMID:18561914, PMID:24726366). Its two-domain architecture underlies this bifunctionality: an N-terminal saposin-like lipid-binding domain and a natively unfolded C-terminal SAP/CXXC domain homologous to the Bax inhibitor Ku70, with both domains required for full activity in vivo (PMID:19258449, PMID:21047780, PMID:24019940). Intracellularly, the SAP domain binds the nucleotide-binding domain of ADP-bound BiP, stabilizing the ADP conformation and inhibiting client release, and ATP binding to MANF disrupts this interaction (PMID:30710085, PMID:33460650); MANF also directly binds the UPR sensor IRE1α, reducing its oligomerization and phosphorylation and dampening XBP1 splicing, and this IRE1α interaction — distinct from BiP binding — is required for dopaminergic neuroprotection (PMID:36739529). MANF expression is induced by ER stress through ERSE elements and an XBP1s-driven positive feedback loop (PMID:17507765, PMID:29649564). The C-terminal RTDL signal mediates ER retention and stress-responsive secretion via KDEL receptors (PMID:23255601). Extracellularly, MANF acts through the cell-surface receptor Neuroplastin to suppress NF-κB signaling and competes with S100A9 for S100A8 to brake TLR4–NF-κB macrophage activation, promoting anti-inflammatory immune phenotypes and tissue repair (PMID:27365452, PMID:33299977, PMID:37799387), and engages PI3K/Akt/mTOR, ERK/mTOR, STAT3, AMPK, and p38 MAPK signaling in a context-dependent manner to promote neurite outgrowth, autophagy, and metabolic regulation (PMID:29050872, PMID:33071755, PMID:37838725, PMID:33856409). Loss of MANF causes chronic UPR activation with progressive β-cell death and diabetes, impaired neurite outgrowth and neuronal migration, and tissue-specific liver and inflammatory pathology (PMID:24726366, PMID:29082311, PMID:31489403). Homozygous loss-of-function MANF mutations cause childhood-onset diabetes with a neurodevelopmental disorder (PMID:33500254).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2003 Medium

    Established MANF as a secreted factor with selective trophic activity, defining the founding functional question of how a non-canonical protein protects specific neuron populations.

    Evidence Recombinant protein with in vitro dopaminergic neuron survival assays comparing MANF, GDNF, and BDNF

    PMID:12794311

    Open questions at the time
    • No receptor or molecular mechanism for selectivity identified
    • Single cell-line-derived source
    • No structural basis for activity
  2. 2008 High

    Positioned MANF within the UPR by showing ER stress induces it and its loss/gain reciprocally modulates stress survival, recasting the trophic factor as a UPR effector.

    Evidence siRNA knockdown, overexpression, ER/Golgi immunofluorescence, viability assays, and rat ischemia model

    PMID:18561914

    Open questions at the time
    • Molecular target within the UPR unknown
    • Mechanism of cytoprotection not defined
    • Secreted vs. intracellular roles not separated
  3. 2010 High

    Resolved the structural basis of MANF's bifunctionality, distinguishing a lipid-binding N-domain from a Ku70-like SAP/CXXC C-domain implicated in apoptosis suppression and redox activity.

    Evidence X-ray crystallography and NMR solution structures with cellular neuroprotection assays of full-length and C-terminal constructs

    PMID:19258449 PMID:20214902 PMID:21047780

    Open questions at the time
    • No binding partner for either domain identified
    • Mechanism of SAP-domain neuroprotection unresolved
    • Functional ligand of the saposin-like domain unknown
  4. 2012 High

    Defined how MANF balances ER retention against secretion, showing the RTDL signal and KDEL receptors gate stress-responsive release.

    Evidence RTDL deletion constructs, KDELR overexpression, peptide competition, and imaging in neuroblastoma and primary cortical neurons

    PMID:23255601

    Open questions at the time
    • Surface KDELR-MANF signaling consequences not defined
    • Trigger linking ER stress to surface KDELR increase unclear
  5. 2013 High

    Demonstrated through in vivo genetic rescue that both MANF domains are jointly required, establishing the protein acts as an integrated bifunctional unit rather than two separable activities.

    Evidence Transgenic rescue of DmManf null with domain-deletion and CXXC point mutants plus mammalian neuron assays

    PMID:24019940

    Open questions at the time
    • Molecular partners of each domain not identified in this system
    • Mechanistic basis of domain interdependence unresolved
  6. 2014 High

    Identified MANF as essential for pancreatic β-cell proliferation and survival, linking its UPR-modulating function to a defined organ phenotype (diabetes).

    Evidence MANF knockout mice, recombinant MANF proliferation assays, and pancreatic overexpression in diabetic mice

    PMID:24726366

    Open questions at the time
    • Molecular mechanism of proliferative effect not defined
    • Secreted vs. intracellular contributions not separated
  7. 2017 Medium

    Extended MANF function beyond cytoprotection to neural progenitor migration/differentiation and central metabolic control, revealing context-dependent signaling outputs.

    Evidence MANF KO NSCs, in utero electroporation, STAT3/ERK Western blots, and hypothalamic viral gain/loss-of-function with PIP4k2b assays

    PMID:28924165 PMID:29050872 PMID:29082311

    Open questions at the time
    • Receptor mediating progenitor signaling not defined
    • Connection between ER role and surface signaling unclear
    • Generality across cell types untested
  8. 2019 High

    Solved the central intracellular mechanism by showing the SAP domain binds ADP-bound BiP's nucleotide-binding domain and inhibits nucleotide exchange, stabilizing chaperone-client complexes.

    Evidence Crystal structures of MANF SAP–BiP NBD complex, in vitro nucleotide exchange assays, and BiP complex analysis in MANF-null cells

    PMID:30710085

    Open questions at the time
    • Cellular consequence of stabilized BiP complexes incompletely defined
    • Whether BiP regulation accounts for all protective effects unresolved
  9. 2020 Medium

    Identified Neuroplastin as a cell-surface MANF receptor coupling extracellular MANF to NF-κB suppression, providing a receptor for the secreted anti-inflammatory function.

    Evidence Co-immunoprecipitation, surface binding assays, NPTN manipulation, and NF-κB reporter assays

    PMID:33299977

    Open questions at the time
    • Single lab, no reciprocal in vivo receptor validation
    • Downstream signaling between NPTN and NF-κB not mapped
  10. 2021 High

    Established that MANF is a broad UPR regulator with an ER interactome beyond BiP, that ATP binding gates the BiP interaction, and that human LOF mutations cause a Mendelian disease, validating its physiological essentiality.

    Evidence AP-MS interactome, microscale thermophoresis/NMR ATP binding, neuronal mutant assays; human genetics with hESC β-cell KO and xenotransplantation

    PMID:33460650 PMID:33500254

    Open questions at the time
    • Functional roles of most interactome partners undefined
    • How distinct activities map to disease phenotypes unresolved
  11. 2023 High

    Defined direct MANF–IRE1α binding as a BiP-independent mechanism that restrains the IRE1α UPR branch and is specifically required for dopaminergic neuroprotection in vivo.

    Evidence Co-IP, binding-interface mutagenesis, IRE1α oligomerization/phosphorylation and XBP1 splicing assays, and 6-OHDA PD model with MANF mutants

    PMID:36739529

    Open questions at the time
    • Relative in vivo weighting of IRE1α vs. BiP mechanisms across tissues unresolved
    • Structural basis of MANF-IRE1α interface not solved
  12. 2024 Medium

    Revealed a non-canonical mitochondrial role in which de-SUMOylated MANF restores Parkin E3 ligase activity via its CXXC motif to drive mitophagy, expanding MANF function beyond the ER.

    Evidence SENP1 manipulation, MANF-PRKN Co-IP, ubiquitin ligase activity and mitophagy assays, CXXC mutagenesis in breast cancer cells

    PMID:39147386

    Open questions at the time
    • Single lab; physiological generality of mitochondrial MANF untested
    • Trafficking route to mitochondria unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MANF's distinct intracellular (BiP, IRE1α, mitochondrial Parkin) and extracellular (Neuroplastin, S100A8) activities are coordinated and weighted within a given cell type to produce tissue-specific protection remains unresolved.
  • No unified model integrating ER, secreted, and mitochondrial functions
  • Receptor-to-signaling cascades incompletely mapped
  • Determinants of tissue-specific phenotype selection unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0140657 ATP-dependent activity 2 GO:0008289 lipid binding 1 GO:0048018 receptor ligand activity 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2 GO:0005739 mitochondrion 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2
Partners
ERN1HSPA5MATN3NPTNPRKNS100A8XBP1

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 MANF (initially derived from a rat mesencephalic type-1 astrocyte cell line) is a secreted ~20 kDa protein that selectively protects nigral dopaminergic neurons in vitro, with greater selectivity than GDNF or BDNF at low-to-middle concentrations; contains two conserved domains and eight cysteines conserved from C. elegans to human. Recombinant protein production, in vitro neuronal survival assays comparing MANF, GDNF, and BDNF dose-response on dopaminergic vs. GABAergic/serotonergic neurons Journal of molecular neuroscience : MN Medium 12794311
2007 Mouse ARMET/MANF is an 18 kDa soluble ER protein that, after signal-sequence cleavage, contains four intramolecular disulfide bonds including two in CXXC sequences; its UPR-dependent transcriptional induction is regulated by an ERSE-II element (identical to the HERP gene ERSE-II) in the MANF promoter. Western blotting, in vitro disulfide-bond characterization, reporter gene assay with MANF promoter deletion constructs Cell structure and function High 17507765
2008 ARMET/MANF protein is upregulated by multiple forms of ER stress in several cell lines and by cerebral ischemia in rat; it localizes to the ER and Golgi and is also secreted; siRNA-mediated silencing increases susceptibility to ER stress-induced death and paradoxically increases proliferation, while overexpression inhibits proliferation and improves viability under stress, establishing MANF as a secreted mediator of the adaptive UPR pathway. siRNA knockdown, overexpression, immunofluorescence (ER/Golgi localization), cell viability assays, immunohistochemistry in rat ischemia model Experimental cell research High 18561914
2009 Crystal structures of human MANF and CDNF reveal that neither resembles known growth factors; the N-terminal domain is a saposin-like lipid-binding domain (suggesting membrane/lipid interaction), while the natively unfolded C-terminal domain of MANF contains a CKGC disulfide bridge analogous to reductases/disulfide isomerases, consistent with a role in ER stress response. Three residues (I10, E79, K88 in MANF) may account for functional differences between MANF and CDNF. X-ray crystallography (crystal structures of both proteins solved), structural bioinformatics Protein engineering, design & selection : PEDS High 19258449
2010 Solution NMR structure of human MANF shows the C-terminal domain (C-MANF) is homologous to the SAP domain of Ku70, a known inhibitor of pro-apoptotic Bax; cellular experiments confirm that both full-length MANF and C-MANF protect neurons intracellularly as efficiently as Ku70. NMR structure determination, cellular neuroprotection assays with MANF and C-MANF constructs The Journal of biological chemistry High 21047780
2010 Solution structure of mouse ARMET/MANF (by NMR relaxation and trypsin digestion) reveals an entirely α-helical two-domain architecture in which the N-terminal and C-terminal domains tumble independently; positive charges are dispersed across both domains and the linker, suggesting a negatively-charged ligand-binding mode. NMR solution structure, 15N relaxation experiments, trypsin digestion FEBS letters High 20214902
2012 The C-terminal RTDL sequence of MANF is required for both ER retention and stress-responsive secretion; KDEL receptor (KDELR) overexpression reduces MANF secretion only when RTDL is present; MANF binds to KDELRs at the plasma membrane surface (inhibited by a KDELR-interacting peptide), and surface KDELR levels increase after ER stress. Lentiviral vector constructs with/without RTDL, KDELR overexpression, peptide competition, immunofluorescence, neuroblastoma cells and primary cortical neurons The Journal of biological chemistry High 23255601
2013 In Drosophila, only full-length MANF containing both N-terminal saposin-like and C-terminal SAP domains rescues larval lethality of DmManf null mutants; neither domain alone (even co-expressed) is sufficient; deleting the signal peptide or mutating the CXXC motif in the C-terminal domain destroys activity; positively charged surface residues and the C-terminal ER retention signal are necessary for rescue when expression is restricted. Transgenic rescue experiments in DmManf mutant background, domain-deletion and point-mutation constructs, in vitro sympathetic neuron survival assay PloS one High 24019940
2014 MANF is indispensable for pancreatic β-cell proliferation and survival in mice: MANF-deficient mice develop progressive postnatal loss of β-cell mass causing diabetes, with chronic UPR activation in islets; recombinant MANF enhances β-cell proliferation in vitro; MANF overexpression in diabetic mouse pancreas enhances β-cell regeneration. MANF knockout mice (loss-of-function), in vitro proliferation assays with recombinant MANF, in vivo pancreatic MANF overexpression in diabetic mice, UPR marker analysis Cell reports High 24726366
2014 Reduced chaperone (Hsc70) activity with aging leads to decreased association of mutant TBP with XBP1s, reducing XBP1s-driven transcription of MANF; overexpression of MANF ameliorates Purkinje cell degeneration via PKC-dependent signaling; Hsc70 overexpression restores TBP-XBP1s interaction and MANF transcription. SCA17 knockin mice with tamoxifen-inducible expression, co-IP (TBP-XBP1s interaction), Hsc70 overexpression, PKC inhibitor studies, viral MANF overexpression Neuron High 24462098
2016 PDGF-like signaling induces MANF expression in innate immune cells of damaged retina (in both flies and mice); MANF promotes alternative (M2) activation of innate immune cells, enhancing neuroprotection and tissue repair, and improves photoreceptor replacement therapy success. Genetic epistasis in Drosophila retina damage model, mouse retinal damage model, MANF gain/loss-of-function, immune cell phenotyping, photoreceptor transplantation assay Science (New York, N.Y.) High 27365452
2016 In Drosophila, Manf shows genetic interactions with GRP78 (Hsc70-3), PERK (PEK), and XBP1 homologs, placing DmManf as a regulator of the UPR; DmManf expression is upregulated by pharmacological ER stress inducers, a response conserved between Drosophila and mammals. Genetic interaction assays (double mutant/RNAi combinations), drug-induced ER stress, reporter gene expression PloS one Medium 26975047
2017 MANF is highly enriched in hypothalamic nuclei and its expression is upregulated by fasting; increasing hypothalamic MANF promotes hyperphagia, decreasing it causes hypophagia; mechanistically, MANF enhances ER localization and activity of PIP4k2b kinase, thereby triggering hypothalamic insulin resistance. Viral vector-mediated overexpression and knockdown in mouse hypothalamus, food intake/body weight measurements, PIP4k2b co-localization and activity assays Nature communications Medium 28924165
2017 MANF-deficient neural stem cells show no proliferation defect but exhibit impaired neurite extension upon differentiation; in vivo MANF deletion causes slower neuronal migration and impaired neurite outgrowth, preceded by reduced de novo protein synthesis and constitutively activated UPR pathways. MANF knockout NSC cultures, in utero electroporation/cortical migration assay, neurite outgrowth measurement, protein synthesis assay, UPR pathway marker analysis eNeuro High 29082311
2017 MANF promotes differentiation and migration of neural progenitor cells (NPCs) in vitro through activation of STAT3 and ERK1/2; in SVZ explants, MANF overexpression facilitates cell migration via STAT3 and ERK1/2; in vivo, intracerebroventricular MANF promotes migration of DCX+ neuroblasts after stroke. NSC/NPC culture with recombinant MANF, SVZ explant migration assay, STAT3/ERK phosphorylation Western blot, rat cortical stroke model with ICV injection Molecular therapy : the journal of the American Society of Gene Therapy Medium 29050872
2018 In human β-cells, exogenous recombinant MANF reduces cytokine-induced cell death by ~38%; the protective effect is associated with repression of NF-κB signaling and amelioration of ER stress; MANF knockdown aggravates ER stress after cytokine challenge. Primary human islets + recombinant MANF, siRNA knockdown in EndoC-βH1 cells, cell viability, global transcriptomics, NF-κB pathway analysis Diabetologia Medium 30032427
2019 The SAP domain of MANF selectively associates with the nucleotide-binding domain (NBD) of ADP-bound BiP; crystal structures show the SAP domain engages the cleft between NBD subdomains Ia and IIa, stabilizing ADP-bound conformation and clashing with the ATP-bound interdomain linker; MANF inhibits both ADP release from and ATP binding to BiP, thereby inhibiting client release; cells lacking MANF have fewer ER stress-induced BiP-containing high-molecular-weight complexes. Crystal structures of MANF SAP domain–BiP NBD complex, in vitro nucleotide exchange assays, MANF knockout cells, size-exclusion chromatography of BiP complexes Nature communications High 30710085
2019 MANF deficiency in flies causes enhanced inflammation and shorter lifespan; MANF deficiency in mice causes inflammatory phenotypes and progressive liver damage (fibrosis, steatosis); immune cell-derived MANF specifically protects against liver inflammation and fibrosis, while hepatocyte-derived MANF prevents hepatosteatosis; liver rejuvenation by heterochronic parabiosis depends on MANF. Drosophila MANF overexpression/KO, MANF heterozygous mice, tissue-specific MANF deletion (immune cells vs. hepatocytes), heterochronic parabiosis, recombinant MANF supplementation Nature metabolism High 31489403
2020 Brain-specific MANF deletion exacerbates ethanol-induced neuronal apoptosis and ER stress; blocking ER stress abrogates the detrimental effects of MANF deficiency on ethanol-induced apoptosis, placing MANF upstream of ER stress in ethanol neurotoxicity; in a tunicamycin-induced neurodegeneration model, MANF deficiency potentiates ER stress and neurodegeneration. CNS-specific Manf knockout mice, tunicamycin and ethanol in vivo models, ER stress marker analysis, RNA-seq Neurobiology of disease Medium 33296727
2020 MANF loss causes prolonged activation of the IRE1α branch of the UPR (and in aged mice additionally PERK and ATF6 branches) without causing dopaminergic neuron loss in the substantia nigra or behavioral changes; cortical neurons lacking MANF are more vulnerable to additional ER stress in vitro, indicating endogenous MANF is required for neuronal ER homeostasis maintenance. Brain-specific MANF knockout mice, UPR marker analysis at multiple ages, stereological neuron counting in SN, dopamine measurement, cortical neuron cultures with ER stress challenge eNeuro High 32005751
2020 Neuroplastin (NPTN) is a cell-surface receptor for MANF; biochemical analysis shows physiological interaction between MANF and NPTN on the cell surface; MANF binding to NPTN suppresses NF-κB signaling, mitigating inflammatory response and apoptosis. Co-immunoprecipitation, surface binding assays, NPTN knockdown/overexpression, NF-κB reporter assays iScience Medium 33299977
2020 MANF regulates neurite outgrowth by activating Akt/mTOR and Erk/mTOR signaling pathways; MANF KO N2a cells fail to grow neurites on RA stimulation, and this is rescued by MANF overexpression or exogenous MANF; pharmacological blockade of Akt, Erk, or mTOR eliminates the MANF-promoting effect on neurite outgrowth. CRISPR/Cas9 MANF KO in N2a cells, siRNA in SH-SY5Y, adenoviral MANF overexpression, pharmacological inhibitors of Akt/Erk/mTOR, Western blot for pathway activation Frontiers in molecular neuroscience Medium 33071755
2021 MANF promotes neuronal survival as a general UPR regulator affecting multiple UPR pathways simultaneously, independently of its role as a GRP78 cofactor; MANF interacts with a conserved set of 15 ER proteins including GRP78, GRP170, PDIA1, and PDIA6; ATP binding to MANF (confirmed by MST and NMR) blocks the MANF-GRP78 interaction; antiapoptotic activity of MANF mutants in neurons reveals divergent roles as GRP78 cofactor vs. antiapoptotic UPR regulator. AP-MS interactome from two mammalian cell lines, microscale thermophoresis (ATP binding), NMR, neuronal apoptosis assays with MANF mutants The Journal of biological chemistry High 33460650
2021 Loss-of-function mutations in the MANF gene in humans cause childhood-onset diabetes with neurodevelopmental disorder; MANF knockout in human embryonic stem cell-derived β-cells induces mild ER stress and impairs insulin-processing capacity; upon implantation in diabetic mice, MANF-KO grafts show elevated ER stress and functional failure. Human genetic (homozygous LOF mutations), hESC MANF knockout, β-cell differentiation, insulin processing assay, xenotransplantation in immunocompromised diabetic mice Diabetes High 33500254
2021 XBP1s (spliced XBP1) binds to ERSE-I in the MANF promoter to promote MANF transcription; MANF in turn interacts with XBP1s to enhance its own expression in a positive feedback loop; IRE1α endonuclease inhibition or XBP1s knockdown attenuates MANF expression. ChIP, promoter reporter assay, XBP1s overexpression and siRNA knockdown, IRE1α inhibitor, co-IP of MANF with XBP1s The international journal of biochemistry & cell biology Medium 29649564
2021 Liver-specific MANF overexpression protects against high-fat diet-induced obesity and promotes browning (beige adipogenesis) of inguinal WAT; mechanistically, MANF directly promotes white adipocyte browning via the p38 MAPK pathway; p38 MAPK blockade abolishes MANF-induced browning; liver-specific MANF KO impairs WAT browning and worsens diet-induced obesity. Liver-specific overexpression and KO mouse models, p38 MAPK inhibitor, primary white adipocyte culture with recombinant MANF, thermogenesis markers The Journal of experimental medicine High 33856409
2022 MANF is transcriptionally induced in cardiomyocytes by liganded estrogen receptor β and inhibited by androgen receptor; ICI (immune checkpoint inhibitor) treatment reduces serum estradiol, decreasing cardiac MANF/HSPA5; heart-specific MANF deletion amplifies ICI myocarditis, and recombinant MANF protein attenuates it, establishing a causal role. Genetic cardiac-specific Manf deletion, recombinant MANF administration, ERβ agonist and androgen depletion in vivo, transcriptional regulation analysis Science translational medicine High 36322628
2023 MANF directly interacts with the ER transmembrane UPR sensor IRE1α; wild-type MANF (but not its IRE1α-binding-deficient mutant) decreases IRE1α oligomerization and phosphorylation, reduces XBP1 splicing, ATF6 and TXNIP levels, and protects neurons from ER stress-induced death; MANF-IRE1α interaction (not MANF-BiP interaction) is required for protection of dopamine neurons in a Parkinson's disease animal model. Co-IP of MANF with IRE1α, binding-interface mutagenesis, IRE1α oligomerization/phosphorylation assays, XBP1 splicing reporter, neuronal apoptosis assays, 6-OHDA rat PD model with MANF mutant constructs Cell reports High 36739529
2023 MANF overexpression in kidney tubular cells stimulates autophagy/mitophagy and mitochondrial biogenesis through p-AMPK enhancement, clears mutant UMOD aggregates, and suppresses cGAS-STING activation; genetic ablation of tubular MANF worsens autophagy suppression and kidney fibrosis in a ADTKD-UMOD mouse model. Inducible tubular MANF overexpression and knockout in ADTKD-UMOD mice, autophagy/mitophagy markers, AMPK phosphorylation, cGAS-STING pathway analysis, mutant UMOD clearance Nature communications High 37838725
2023 MANF brakes macrophage TLR4 signaling by competitively binding S100A8, preventing S100A8/A9 heterodimer formation and thereby inhibiting S100A8/A9-mediated TLR4-NF-κB activation; myeloid-specific MANF KO increases hepatic Ly6Chigh pro-inflammatory macrophages and worsens hepatic fibrosis. Myeloid-specific MANF KO mice, competitive binding assay (MANF vs. S100A9 for S100A8), Co-IP, macrophage phenotyping, TLR4-NF-κB pathway analysis, recombinant MANF treatment Acta pharmaceutica Sinica. B High 37799387
2024 Under glucose starvation, SENP1-mediated de-SUMOylation of MANF inhibits its nuclear translocation and increases cytoplasmic/mitochondrial MANF; mitochondrial MANF binds to PRKN (Parkin) E3 ligase, alleviates oxidative inhibition of PRKN's RING II domain via its CXXC motif, restores PRKN E3 ligase activity, and thereby mediates mitophagy to promote breast cancer cell survival. SENP1 manipulation (de-SUMOylation), Co-IP of MANF-PRKN, PRKN ubiquitin ligase activity assay, CXXC motif mutagenesis, mitophagy assays, MANF subcellular fractionation Autophagy Medium 39147386
2013 ARMET/MANF interacts with mutant matrilin-3 (but not COMP) in chondrocyte ER stress models of skeletal dysplasia, establishing substrate specificity; both ARMET and CRELD2 are secreted into ECM following ER stress; substrate-trapping experiments confirmed CRELD2 but not ARMET has PDI-like activity. Cell and mouse models of chondrodysplasia, co-IP/substrate trapping, immunohistochemistry, Western blotting; genotype-specific expression analysis Human molecular genetics Medium 23956175
2017 THBS1 (thrombospondin 1) maintains MANF expression in β-cells exposed to cytokines or thapsigargin, and this THBS1-MANF axis prevents BIM-dependent mitochondrial apoptosis; prolonged stress leads to THBS1 and MANF degradation and loss of this prosurvival mechanism. THBS1 overexpression/silencing in rat/mouse/human β-cells, Western blot for MANF and BIM, apoptosis assays, ER stress induction The Journal of biological chemistry Medium 28698383
2022 CDNF and MANF display functional redundancy in skeletal muscle (CDNF deficiency increases UPR activation, aggravated by combined MANF loss) but not in brain; neither single nor combined brain-specific KO causes dopaminergic neuron degeneration, showing tissue-specific UPR regulation. Cdnf−/−, Manf−/−, and double KO mice, UPR markers in multiple tissues, dopaminergic neuron counting Cellular and molecular life sciences : CMLS Medium 35129674

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. Journal of molecular neuroscience : MN 295 12794311
2008 Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Experimental cell research 237 18561914
2016 Immune modulation by MANF promotes tissue repair and regenerative success in the retina. Science (New York, N.Y.) 194 27365452
2014 MANF is indispensable for the proliferation and survival of pancreatic β cells. Cell reports 170 24726366
2008 MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain. Molecular and cellular neurosciences 158 18718866
2007 ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element. Cell structure and function 156 17507765
2010 Novel CDNF/MANF family of neurotrophic factors. Developmental neurobiology 150 20186704
2016 Unconventional neurotrophic factors CDNF and MANF: Structure, physiological functions and therapeutic potential. Neurobiology of disease 144 27425895
2012 Mesencephalic astrocyte-derived neurotrophic factor (MANF) secretion and cell surface binding are modulated by KDEL receptors. The Journal of biological chemistry 124 23255601
2010 Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons. The Journal of biological chemistry 121 21047780
2019 MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage. Nature metabolism 110 31489403
2009 The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional. Protein engineering, design & selection : PEDS 105 19258449
2009 Induction profile of MANF/ARMET by cerebral ischemia and its implication for neuron protection. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 100 19773801
2014 Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in inducible SCA17 mice. Neuron 92 24462098
2019 MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP. Nature communications 90 30710085
2012 MANF regulates dopaminergic neuron development in larval zebrafish. Developmental biology 84 22898306
2015 Armet is an effector protein mediating aphid-plant interactions. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 81 25678626
2017 MANF Promotes Differentiation and Migration of Neural Progenitor Cells with Potential Neural Regenerative Effects in Stroke. Molecular therapy : the journal of the American Society of Gene Therapy 77 29050872
2010 Widespread cortical expression of MANF by AAV serotype 7: localization and protection against ischemic brain injury. Experimental neurology 74 20685313
2018 MANF protects human pancreatic beta cells against stress-induced cell death. Diabetologia 73 30032427
2019 Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against Aβ toxicity via attenuating Aβ-induced endoplasmic reticulum stress. Journal of neuroinflammation 71 30760285
2013 Armet/Manf and Creld2 are components of a specialized ER stress response provoked by inappropriate formation of disulphide bonds: implications for genetic skeletal diseases. Human molecular genetics 71 23956175
2014 Enhanced efficacy of the CDNF/MANF family by combined intranigral overexpression in the 6-OHDA rat model of Parkinson's disease. Molecular therapy : the journal of the American Society of Gene Therapy 68 25369767
2018 Poststroke delivery of MANF promotes functional recovery in rats. Science advances 67 29806020
2010 Functions for the cardiomyokine, MANF, in cardioprotection, hypertrophy and heart failure. Journal of molecular and cellular cardiology 66 20970425
2015 Therapeutic potential of the endoplasmic reticulum located and secreted CDNF/MANF family of neurotrophic factors in Parkinson's disease. FEBS letters 63 26450777
2020 Neuroplastin Modulates Anti-inflammatory Effects of MANF. iScience 62 33299977
2021 Feeding-induced hepatokine, Manf, ameliorates diet-induced obesity by promoting adipose browning via p38 MAPK pathway. The Journal of experimental medicine 60 33856409
2023 MANF regulates neuronal survival and UPR through its ER-located receptor IRE1α. Cell reports 58 36739529
2017 MANF Is Essential for Neurite Extension and Neuronal Migration in the Developing Cortex. eNeuro 57 29082311
2019 Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Is Highly Expressed in Mouse Tissues With Metabolic Function. Frontiers in endocrinology 56 31781038
2021 Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress. Diabetes 55 33500254
2022 Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis. Science translational medicine 54 36322628
2020 MANF Promotes Diabetic Corneal Epithelial Wound Healing and Nerve Regeneration by Attenuating Hyperglycemia-Induced Endoplasmic Reticulum Stress. Diabetes 53 32312869
2017 MANF regulates hypothalamic control of food intake and body weight. Nature communications 51 28924165
2021 The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor. The Journal of biological chemistry 50 33460650
2018 MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice. Diabetes 50 30305368
2023 MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice. Nature communications 49 37838725
2019 Armet, an aphid effector protein, induces pathogen resistance in plants by promoting the accumulation of salicylic acid. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 48 30967016
2018 MANF protects dopamine neurons and locomotion defects from a human α-synuclein induced Parkinson's disease model in C. elegans by regulating ER stress and autophagy pathways. Experimental neurology 48 29959908
2017 Nrf2-mediated neuroprotection by MANF against 6-OHDA-induced cell damage via PI3K/AKT/GSK3β pathway. Experimental gerontology 48 29079145
2020 Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss. Cell death & disease 47 32029702
2017 Pancreatic β-cell protection from inflammatory stress by the endoplasmic reticulum proteins thrombospondin 1 and mesencephalic astrocyte-derived neutrotrophic factor (MANF). The Journal of biological chemistry 45 28698383
2020 MANF is neuroprotective against ethanol-induced neurodegeneration through ameliorating ER stress. Neurobiology of disease 44 33296727
2020 Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling. World journal of stem cells 43 32843919
2018 XBP1 activation enhances MANF expression via binding to endoplasmic reticulum stress response elements within MANF promoter region in hepatitis B. The international journal of biochemistry & cell biology 43 29649564
2023 MANF brakes TLR4 signaling by competitively binding S100A8 with S100A9 to regulate macrophage phenotypes in hepatic fibrosis. Acta pharmaceutica Sinica. B 41 37799387
2020 Trophic activities of endoplasmic reticulum proteins CDNF and MANF. Cell and tissue research 41 32845431
2014 Spatiotemporal expression of MANF in the developing rat brain. PloS one 41 24587361
2018 Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Protects Against Neuronal Apoptosis via Activation of Akt/MDM2/p53 Signaling Pathway in a Rat Model of Intracerebral Hemorrhage. Frontiers in molecular neuroscience 40 29896089
2022 Mesencephalic astrocyte-derived neurotrophic factor (MANF): Structure, functions and therapeutic potential. Ageing research reviews 38 36272696
2013 Characterization of the structural and functional determinants of MANF/CDNF in Drosophila in vivo model. PloS one 38 24019940
2022 MANF: an emerging therapeutic target for metabolic diseases. Trends in endocrinology and metabolism: TEM 37 35135706
2020 Hepatocyte-derived MANF alleviates hepatic ischaemia-reperfusion injury via regulating endoplasmic reticulum stress-induced apoptosis in mice. Liver international : official journal of the International Association for the Study of the Liver 36 33064897
2017 Mesencephalic astrocyte-derived neurotrophic factor (MANF), a new player in endoplasmic reticulum diseases: structure, biology, and therapeutic roles. Translational research : the journal of laboratory and clinical medicine 36 28719799
2022 Armet from whitefly saliva acts as an effector to suppress plant defences by targeting tobacco cystatin. The New phytologist 35 35238409
2020 MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System. eNeuro 35 32005751
2020 Mono-macrophage-Derived MANF Protects Against Lipopolysaccharide-Induced Acute Kidney Injury via Inhibiting Inflammation and Renal M1 Macrophages. Inflammation 35 33145627
2018 MANF improves the MPP+/MPTP-induced Parkinson's disease via improvement of mitochondrial function and inhibition of oxidative stress. American journal of translational research 35 29887945
2018 C. elegans MANF Homolog Is Necessary for the Protection of Dopaminergic Neurons and ER Unfolded Protein Response. Frontiers in neuroscience 33 30147641
2016 Exploring the Conserved Role of MANF in the Unfolded Protein Response in Drosophila melanogaster. PloS one 33 26975047
2023 MANF ameliorates DSS-induced mouse colitis via restricting Ly6ChiCX3CR1int macrophage transformation and suppressing CHOP-BATF2 signaling pathway. Acta pharmacologica Sinica 31 36635421
2018 Trophic Factors in Inflammation and Regeneration: The Role of MANF and CDNF. Frontiers in physiology 31 30515104
2014 MANF silencing, immunity induction or autophagy trigger an unusual cell type in metamorphosing Drosophila brain. Cellular and molecular life sciences : CMLS 29 25511196
2024 MANF facilitates breast cancer cell survival under glucose-starvation conditions via PRKN-mediated mitophagy regulation. Autophagy 28 39147386
2020 DHA modulates MANF and TREM2 abundance, enhances neurogenesis, reduces infarct size, and improves neurological function after experimental ischemic stroke. CNS neuroscience & therapeutics 28 32757264
2012 Valproic acid up-regulates melatonin MT1 and MT2 receptors and neurotrophic factors CDNF and MANF in the rat brain. The international journal of neuropsychopharmacology 28 22243807
2022 Dendrobine inhibits dopaminergic neuron apoptosis via MANF-mediated ER stress suppression in MPTP/MPP+-induced Parkinson's disease models. Phytomedicine : international journal of phytotherapy and phytopharmacology 27 35636177
2020 Liraglutide protects pancreatic β cells from endoplasmic reticulum stress by upregulating MANF to promote autophagy turnover. Life sciences 27 32275937
2023 Aging disrupts MANF-mediated immune modulation during skeletal muscle regeneration. Nature aging 26 37118549
2022 CDNF and MANF regulate ER stress in a tissue-specific manner. Cellular and molecular life sciences : CMLS 25 35129674
2018 Photoreceptor Protection by Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF). eNeuro 25 29687079
2018 Emerging Roles for Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) in Pancreatic Beta Cells and Diabetes. Frontiers in physiology 25 30386256
2020 Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Regulates Neurite Outgrowth Through the Activation of Akt/mTOR and Erk/mTOR Signaling Pathways. Frontiers in molecular neuroscience 24 33071755
2020 Hepatocyte-derived MANF is protective for rifampicin-induced cholestatic hepatic injury via inhibiting ATF4-CHOP signal activation. Free radical biology & medicine 24 33127565
2010 Solution structure and dynamics of mouse ARMET. FEBS letters 24 20214902
2020 Molecular profile of the rat peri-infarct region four days after stroke: Study with MANF. Experimental neurology 23 32229226
2018 MANF attenuates neuronal apoptosis and promotes behavioral recovery via Akt/MDM-2/p53 pathway after traumatic spinal cord injury in rats. BioFactors (Oxford, England) 23 29797541
2016 A Comparative Analysis of the Molecular Features of MANF and CDNF. PloS one 23 26820513
2016 MRI Dynamically Evaluates the Therapeutic Effect of Recombinant Human MANF on Ischemia/Reperfusion Injury in Rats. International journal of molecular sciences 22 27608005
2022 Cold Plasma Irradiation Attenuates Atopic Dermatitis via Enhancing HIF-1α-Induced MANF Transcription Expression. Frontiers in immunology 21 35911675
2022 Mesencephalic astrocyte-derived neurotrophic factor (MANF) prevents the neuroinflammation induced dopaminergic neurodegeneration. Experimental gerontology 21 36436758
2021 MANF: A Novel Endoplasmic Reticulum Stress Response Protein-The Role in Neurological and Metabolic Disorders. Oxidative medicine and cellular longevity 21 34745419
2023 Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF): An Emerging Therapeutic Target for Neurodegenerative Disorders. Cells 20 37048105
2023 Mesencephalic astrocyte-derived neurotrophic factor (MANF) alleviates cerebral ischemia/reperfusion injury in mice by regulating microglia polarization via A20/NF-κB pathway. International immunopharmacology 20 38134597
2022 MANF in POMC Neurons Promotes Brown Adipose Tissue Thermogenesis and Protects Against Diet-Induced Obesity. Diabetes 20 35972224
2022 MANF/EWSR1/ANXA6 pathway might as the bridge between hypolipidemia and major depressive disorder. Translational psychiatry 19 36585419
2015 ER stress-inducible protein MANF selectively expresses in human spleen. Human immunology 19 26429332
2022 UPR Responsive Genes Manf and Xbp1 in Stroke. Frontiers in cellular neuroscience 18 35783104
2014 A sensitive assay for the biosynthesis and secretion of MANF using NanoLuc activity. Biochemical and biophysical research communications 18 24845376
2021 MANF protects pancreatic acinar cells against alcohol-induced endoplasmic reticulum stress and cellular injury. Journal of hepato-biliary-pancreatic sciences 17 33644980
2021 Increased MANF Expression in the Inferior Temporal Gyrus in Patients With Alzheimer Disease. Frontiers in aging neuroscience 17 33994992
2019 MANF deletion abrogates early larval Caenorhabditis elegans stress response to tunicamycin and Pseudomonas aeruginosa. European journal of cell biology 17 31138438
2015 Analysis of the conserved neurotrophic factor MANF in the Drosophila adult brain. Gene expression patterns : GEP 16 25917377
2021 MANF Is Neuroprotective in Early Stages of EAE, and Elevated in Spinal White Matter by Treatment With Dexamethasone. Frontiers in cellular neuroscience 15 34305531
2018 MANF: A New Player in the Control of Energy Homeostasis, and Beyond. Frontiers in physiology 15 30555354
2023 CDNF and MANF in the brain dopamine system and their potential as treatment for Parkinson's disease. Frontiers in psychiatry 14 37555005
2020 MANF delivery improves retinal homeostasis and cell replacement therapies in ageing mice. Experimental gerontology 14 32119994
2019 Secondary Pathology of the Thalamus after Focal Cortical Stroke in Rats is not Associated with Thermal or Mechanical Hypersensitivity and is Not Alleviated by Intra-Thalamic Post-Stroke Delivery of Recombinant CDNF or MANF. Cell transplantation 14 31037983
2015 Characterization of the Role of MANF in Regulating the Secretion of CRELD2. Biological & pharmaceutical bulletin 14 25947918

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