Neudesin (NENF) is a 172-aa secreted neurotrophic factor belonging to the cytochrome b5/MAPR (membrane-associated progesterone receptor) protein family. The protein contains a cytochrome b5-like heme/steroid-binding domain whose two conserved tyrosines (Tyr-82, Tyr-88) coordinate Fe(III)-protoporphyrin IX (hemin); heme binding is required for neurotrophic activity. Neudesin is secreted from neurons and promotes neuronal survival and differentiation through activation of G-protein-coupled receptors (pertussis-toxin sensitive in primary neurons, indicating a Gi/Go-coupled receptor; no definitive receptor has been identified), triggering MAPK/ERK and PI3K/AKT signaling pathways. Beyond neural functions, neudesin acts as an anorexigenic factor that suppresses appetite through hypothalamic melanocortin signaling (increased Pomc and Mc4r), and is a negative regulator of systemic energy expenditure: KO mice show elevated sympathetic activity, BAT thermogenesis, and WAT lipolysis and are resistant to high-fat-diet-induced obesity. The protein localizes to the endoplasmic reticulum, mitochondria (via interaction with PINK1 and PARK7/DJ-1), and is secreted to the extracellular space. NENF is overexpressed/amplified in multiple cancers including triple-negative breast cancer, where it promotes EMT-linked invasion and metastasis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation for ER localization. Neudesin is a secreted protein with a signal peptide, and endogenous NENF is found in marker-controlled ER fractions of neuronal cells and brain [PMID:31536960], where it associates with PINK1 and PARK7/DJ-1. The ER pool is real but peripheral to the extracellular neurotrophic function. Reason: ORGANELLES ER check (2026-11-05), examined as a synthesis row. The PAINT IBD node PTN000031653 (GO:0005783) is seeded by NENF itself (Q9UMX5), PGRMC2 (O15173) and MAPR-family members from mouse, rat, Arabidopsis and Aspergillus; NENF among its own seeds reflects its IDA row. The organelle claim holds: PMID:31536960 (full text) immunoblots subcellular fractions of NTera2 cells and rodent brain with mt, ER and MAM markers as internal controls and finds endogenous NENF accumulating in the ER fraction. This is a biosynthetic and heme-loading pool of a secreted protein (signal peptide 1-31, no C-terminal KDEL-type retrieval motif, no TM), so under the batch 1 transit rule (direct evidence on the endogenous protein, as for ADIPOQ) it is KEEP_AS_NON_CORE rather than core; the core activity is in the extracellular region. Moved from ACCEPT for that reason and to match the mitochondrion rows (2026-11-03). MARK_AS_OVER_ANNOTATED was considered and rejected because the endogenous protein is shown in a marker-checked ER fraction. No sub-compartment row is added: a soluble signal-peptide protein would be lumenal in transit, but nothing shows residence or retention in the lumen, and one fractionation study does not resolve lumen from MAM. Supporting Evidence: PMID:31536960 PINK1 and DJ-1 immunoprecipitates in whole-cell extract (WCE) as well as in mt, ER, and MAM lysates from ECSCs, DNLCs, and mouse brain PMID:31536960 showed an accumulation of NENF in the mt, endoplasmic reticulum (ER), and mitochondria-associated membrane (MAM) fractions PMID:31536960 mt, ER, and MAM markers (ii) used as internal control file:human/NENF/NENF-deep-research-perplexity.md As a secreted protein with a signal peptide, neudesin is synthesized on membrane-bound ribosomes and undergoes co-translational translocation into the rough endoplasmic reticulum |
| GO:0012505 endomembrane system | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for endomembrane system localization is consistent with neudesin being a secreted protein that transits through the ER and Golgi apparatus. Reason: Neudesin is a secreted protein that passes through the endomembrane system (ER, Golgi) during its synthesis and secretion. This is a parent term to ER and is appropriately annotated for a secretory pathway protein. The IBA annotation provides phylogenetic support for this conserved localization pattern. Supporting Evidence: file:human/NENF/NENF-deep-research-perplexity.md neudesin transit through the classical secretory pathway: from the endoplasmic reticulum to the Golgi apparatus for post-translational modification and packaging into secretory vesicles |
| GO:0016020 membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for membrane localization reflects association with the endomembrane system during secretory pathway transit. Neudesin associates with ER and mitochondrial membranes. Reason: Neudesin is associated with endomembrane system membranes (ER, mitochondria) during its processing and localization. While not a transmembrane protein itself (unlike PGRMC1/PGRMC2 in the same family), it associates with membrane compartments. The IBA annotation is consistent with its subcellular distribution. Supporting Evidence: file:human/NENF/NENF-deep-research-perplexity.md neudesin transit through the classical secretory pathway: from the endoplasmic reticulum to the Golgi apparatus for post-translational modification and packaging into secretory vesicles |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location mapping. Neudesin is a secreted protein released to the extracellular space where it acts on target cells. Reason: Neudesin is definitively a secreted protein with experimental evidence (IDA) for extracellular space localization [PMID:31536960]. The IEA annotation correctly captures this fundamental aspect of neudesin biology. Extracellular region is a parent term to extracellular space. Supporting Evidence: PMID:31536960 NENF secretion in the conditioned medium and cell lysates immunoblotted (IB) with anti-NENF antibody file:human/NENF/NENF-deep-research-perplexity.md Neudesin is a secreted protein comprising 172 amino acids in humans... contains a distinctive N-terminal signal peptide characteristic of secreted proteins |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA annotation for mitochondrial localization is supported by experimental evidence from PMID:31536960 showing NENF is localized to mitochondria via PINK1 and PARK7/DJ-1. Reason: Mitochondrial localization is experimentally validated (IDA from PMID:31536960). The protein interacts with Parkinson disease-related proteins PINK1 and PARK7/DJ-1 at mitochondria and ER-mitochondria associated membranes (MAMs). This IEA annotation is consistent with the experimental evidence. ORGANELLES check (2026-11-03), examined as a synthesis row. GO_REF:0000120 combines ARBA, SL-0173 and mouse Nenf (Q9CQ45); UniProt's curated location rests on PMID:31536960 (ECO:0000269), and the mouse annotations are themselves ISO from human, so the row has a single experimental source, which the IDA row covers. Moved from ACCEPT to KEEP_AS_NON_CORE together with the IDA row, because the core activity (secreted neurotrophic factor) acts in the extracellular region, which is what core_functions record. Supporting Evidence: PMID:31536960 PINK1 and DJ-1 immunoprecipitates in whole-cell extract (WCE) as well as in mt, ER, and MAM lysates from ECSCs, DNLCs, and mouse brain file:human/NENF/NENF-uniprot.txt Mitochondrion {ECO:0000269|PubMed:31536960} |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA annotation for ER localization based on combined automated annotation methods. Supported by experimental evidence showing endogenous NENF in marker-controlled ER fractions, associated with PINK1 and DJ-1; a peripheral pool of a secreted protein. Reason: ORGANELLES ER check (2026-11-05), examined as a synthesis row. GO_REF:0000120 rests here on the UniProt location "Endoplasmic reticulum", curated from PMID:31536960 (ECO:0000269), so the row has the same single experimental source as the IDA row and its organelle claim holds (marker-controlled fractionation of the endogenous protein). Moved from ACCEPT to KEEP_AS_NON_CORE together with the IBA and IDA rows: NENF is a secreted neurotrophic factor (signal peptide, no ER retrieval motif) whose core activity is extracellular. The IEA and IBA are not independent evidence lines; both trace to the same paper. No sub-compartment row (see the IBA row). Supporting Evidence: PMID:31536960 PINK1 and DJ-1 immunoprecipitates in whole-cell extract (WCE) as well as in mt, ER, and MAM lysates from ECSCs, DNLCs, and mouse brain file:human/NENF/NENF-uniprot.txt Endoplasmic reticulum {ECO:0000269|PubMed:31536960} |
| GO:0007165 signal transduction | IEA GO_REF:0000108 | ACCEPT | Summary: IEA annotation based on logical inference from inter-ontology links. Neudesin activates signal transduction through G-protein-coupled receptors, triggering MAPK and PI3K pathways [deep research]. Reason: Signal transduction is a core function of neudesin. The protein acts as a secreted ligand that activates GPCR-mediated signaling cascades including MAPK/ERK and PI3K/AKT pathways. While broad, this term accurately captures neudesin's role as a signaling molecule. Supporting Evidence: file:human/NENF/NENF-deep-research-perplexity.md neudesin promotes the phosphorylation and activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which represent the central effectors of the classical MAPK pathway... This PTX sensitivity indicates that neudesin activates the MAPK pathway through interaction with a Gi/Go-protein-coupled receptor |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: IEA annotation based on UniProt keyword mapping for iron/heme binding. Neudesin contains a cytochrome b5-like heme-binding domain that binds Fe(III)-protoporphyrin IX (hemin) via conserved tyrosine residues (Tyr-82, Tyr-88). Reason: The heme/iron binding capability is real and well-documented, mediated by the cytochrome b5-like domain. However, this is not the primary molecular function of neudesin - it is a growth factor. Heme binding enhances neurotrophic activity but is ancillary to the core function. The term is also very general; a more specific term like GO:0020037 'heme binding' would be more informative. Proposed replacements: heme binding Supporting Evidence: file:human/NENF/NENF-deep-research-perplexity.md The heme-binding functionality of neudesin is mediated by two conserved tyrosine residues, specifically tyrosine-82 and tyrosine-88 in the human sequence, which form the critical iron-binding site within the hydrophobic pocket... The binding of iron(III)-protoporphyrin IX (hemin) to neudesin significantly enhances its neurotrophic activity PMID:18056703 Neudesin is a secreted protein with neurotrophic activity in neurons and undifferentiated neural cells. We report here that neudesin is an extracellular heme-binding protein and that its neurotrophic activity is dependent on the binding of heme to its cytochrome b(5)-like heme/steroid-binding domain. PMID:26042224 Tyrosine residues 82 and 88 in this pocket are essential for heme-binding file:human/NENF/NENF-deep-research-falcon.md A foundational mechanistic study established neudesin as an **extracellular heme-binding protein** whose **neurotrophic activity depends on heme binding** to the **cytochrome b5-like heme/steroid-binding domain** |
| GO:0005615 extracellular space | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara transfer of experimental evidence. Neudesin is a secreted neurotrophic factor that acts in the extracellular space. Reason: Extracellular space localization is a core aspect of neudesin function. The protein is secreted and acts as an extracellular ligand for GPCRs. This is the location where neudesin carries out its primary neurotrophic and signaling functions. Experimental evidence (IDA) from PMID:31536960 confirms this. Supporting Evidence: PMID:31536960 NENF secretion in the conditioned medium and cell lysates immunoblotted (IB) with anti-NENF antibody file:human/NENF/NENF-deep-research-perplexity.md Once secreted, neudesin is expected to act on neighboring cells expressing the appropriate neudesin receptors |
| GO:0008083 growth factor activity | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara transfer. Neudesin is a bona fide neurotrophic factor that promotes neuronal survival, proliferation, and differentiation [deep research]. Reason: Growth factor activity is the core molecular function of neudesin. The protein was originally identified as a neuron-derived neurotrophic factor that promotes neuronal survival in primary cultures and undifferentiated neural cell lines. This is the defining functional property of neudesin. Supporting Evidence: file:human/NENF/NENF-deep-research-perplexity.md Neudesin exhibits robust neurotrophic activity in primary cultured mature neurons derived from embryonic mouse cerebral cortex, where recombinant neudesin significantly enhances neuronal survival by decreasing apoptotic cell death in a concentration-dependent manner PMID:31536960 Model of NENF role with DJ-1 and PINK1 in neurotrophic activity and neuronal survival/death PMID:23805070 Neudesin (neuron-derived neurotrophic factor; NENF) was identified as a neurotrophic factor that is involved in neuronal differentiation and survival. It is abundantly expressed in the central nervous system, and its neurotrophic activity is exerted via the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. PMID:26042224 Neudesin exhibits significant neurotrophic activity in primary cultured neurons, but not mitogenic activity in primary cultured astrocytes, indicating that it is a neurotrophic factor. file:human/NENF/NENF-deep-research-falcon.md Neudesin is described as a neuron-derived neurotrophic factor involved in **neuronal differentiation and survival**, abundantly expressed in the CNS |
| GO:0032099 negative regulation of appetite | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara transfer. Intracerebroventricular administration of neudesin decreases food intake through hypothalamic melanocortin signaling (increased POMC and MC4R expression) [deep research]. Reason: Negative regulation of appetite is a well-documented core biological function of neudesin. Central administration of neudesin suppresses food intake via activation of the melanocortin system in the hypothalamus. This anorexigenic function is conserved and represents a distinct physiological role beyond neural development. Supporting Evidence: file:human/NENF/NENF-deep-research-perplexity.md Administration of recombinant neudesin directly into the lateral cerebral ventricle (intracerebroventricular injection) decreases food intake and reduces body weight in mice. These anorexigenic (appetite-suppressing) effects of neudesin are mediated through activation of the melanocortin signaling system, specifically resulting in increased expression of pro-opiomelanocortin (POMC) mRNA and melanocortin 4 receptor (MC4R) mRNA in the hypothalamus |
| GO:0043410 positive regulation of MAPK cascade | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara transfer. Neudesin activates MAPK/ERK signaling through G-protein-coupled receptors, leading to phosphorylation of ERK1/2 [deep research]. Reason: Positive regulation of MAPK cascade is a core signaling mechanism of neudesin. The protein activates ERK1/2 phosphorylation through Gi/Go-coupled GPCRs (pertussis toxin-sensitive). This pathway mediates neudesin's effects on neuronal survival and proliferation. Supporting Evidence: file:human/NENF/NENF-deep-research-perplexity.md neudesin promotes the phosphorylation and activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which represent the central effectors of the classical MAPK pathway. The phosphorylation of ERK1/2 by neudesin is sensitive to inhibition by pertussis toxin (PTX)... neudesin activates the MAPK pathway through interaction with a Gi/Go-protein-coupled receptor PMID:23805070 The neurotrophic effects of neudesin in primary cultured neurons are exerted via the MAPK and PI-3K pathways. In addition, pertussis toxin (PTX), a Gi/Go protein inhibitor, significantly inhibits the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 by neudesin, indicating that the neurotrophic activity of neudesin may be related to the activation of a Gi/Go protein-coupled receptor file:human/NENF/NENF-deep-research-falcon.md Neudesin activates **MAPK/ERK** and **PI3K/AKT** signaling in multiple contexts, including neuronal systems |
| GO:0005515 protein binding | IPI PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro... | REMOVE | Summary: IPI annotation from PMID:31536960. The study showed NENF interacts with PINK1 and PARK7/DJ-1 at mitochondria and ER-mitochondria associated membranes. However, 'protein binding' is an uninformative term. Reason: While the protein-protein interactions with PINK1 and DJ-1 are experimentally validated, the term 'protein binding' (GO:0005515) does not provide useful functional information. Per curation guidelines, this vague term should be avoided in favor of more specific terms describing the actual biological context of the interaction. Supporting Evidence: PMID:31536960 NENF Binding with DJ-1 and PINK1 Is Vital for Neurotrophic Activity in DNLCs |
| GO:0005615 extracellular space | IDA PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro... | ACCEPT | Summary: IDA annotation from PMID:31536960 showing NENF is secreted and detected in conditioned medium of cells. This is direct experimental evidence for extracellular space localization. Reason: Extracellular space localization is experimentally demonstrated by detection of NENF in conditioned medium. This IDA evidence confirms neudesin's role as a secreted factor that acts in the extracellular environment. Supporting Evidence: PMID:31536960 NENF secretion in the conditioned medium and cell lysates immunoblotted (IB) with anti-NENF antibody |
| GO:0005739 mitochondrion | IDA PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro... | KEEP AS NON CORE | Summary: IDA annotation from PMID:31536960 demonstrating NENF localization to mitochondria via immunoprecipitation from mitochondrial fractions and co-localization studies with mitochondrial markers. Reason: Mitochondrial localization is directly demonstrated by immunoprecipitation from mitochondrial (mt) lysates and co-localization with mitochondrial marker AIF in confocal microscopy. NENF is localized to mitochondria by PINK1 and DJ-1. ORGANELLES check (2026-11-03). The full text separates mt, ER and MAM fractions with marker proteins as internal controls, so the mitochondrial signal is not an unresolved MAM contamination, and the organelle claim holds. The action moves from ACCEPT to KEEP_AS_NON_CORE because neudesin's core activity is as a secreted neurotrophic factor (signal peptide 1-31, extracellular region in core_functions); the mitochondrial pool relates to heme loading via DJ-1/PINK1 and is peripheral. No sub-compartment row is added. The same paper also places NENF in the MAM fraction, but that is one study, and NENF is a soluble signal-peptide protein with no membrane anchor, so a membrane term such as GO:0044233 would not fit its topology without a second line of evidence. Supporting Evidence: PMID:31536960 PINK1 and DJ-1 immunoprecipitates in whole-cell extract (WCE) as well as in mt, ER, and MAM lysates from ECSCs, DNLCs, and mouse brain using anti-PINK1 and DJ-1 antibodies immunoblotted (IB) with anti-NENF antibody PMID:31536960 showed an accumulation of NENF in the mt, endoplasmic reticulum (ER), and mitochondria-associated membrane (MAM) fractions PMID:31536960 mt, ER, and MAM markers (ii) used as internal control |
| GO:0005783 endoplasmic reticulum | IDA PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro... | KEEP AS NON CORE | Summary: IDA annotation from PMID:31536960 demonstrating NENF localization to the ER by immunoblotting of marker-controlled subcellular fractions and by immunoprecipitation from ER lysates, where NENF associates with PINK1 and DJ-1. A real but peripheral pool of a secreted protein. Reason: ER localization is directly demonstrated: endogenous NENF accumulates in the ER fraction (mt, ER and MAM markers as internal controls) and co-immunoprecipitates with PINK1 and DJ-1 from ER lysates. ORGANELLES ER check (2026-11-05). The assay cannot resolve lumen from membrane, so under rule 2 the root term is what the experiment showed. Moved from ACCEPT to KEEP_AS_NON_CORE because NENF is a secreted neurotrophic factor (signal peptide 1-31, no ER retrieval motif) whose core activity is extracellular; the ER pool is its biosynthetic route and the site of a proposed heme-loading association with DJ-1 and PINK1, matching the non-core call on the mitochondrion rows (2026-11-03). No sub-compartment row is added. Supporting Evidence: PMID:31536960 PINK1 and DJ-1 immunoprecipitates in whole-cell extract (WCE) as well as in mt, ER, and MAM lysates from ECSCs, DNLCs, and mouse brain using anti-PINK1 and DJ-1 antibodies immunoblotted (IB) with anti-NENF antibody PMID:31536960 showed an accumulation of NENF in the mt, endoplasmic reticulum (ER), and mitochondria-associated membrane (MAM) fractions PMID:31536960 mt, ER, and MAM markers (ii) used as internal control |
| GO:0032099 negative regulation of appetite | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation based on manual transfer from orthologs (likely mouse). Mouse studies show intracerebroventricular neudesin administration suppresses food intake via hypothalamic melanocortin signaling. Reason: Negative regulation of appetite is well-documented in mouse studies and represents a conserved function. The ISS annotation appropriately transfers this experimentally validated function from mouse to human based on sequence similarity and conserved mechanism of action. Supporting Evidence: file:human/NENF/NENF-deep-research-perplexity.md Administration of recombinant neudesin directly into the lateral cerebral ventricle (intracerebroventricular injection) decreases food intake and reduces body weight in mice PMID:23805070 recombinant neudesin that was administered via an interacerebroventricular cannula decreased food intake and body weight through activation of melanocortin signaling, by increasing the hypothalamic Pomc and Mc4r mRNA expression. file:human/NENF/NENF-deep-research-falcon.md Intracerebroventricular administration of recombinant neudesin reduced food intake and body weight and altered hypothalamic melanocortin-related readouts |
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