ArticleThe Journal of biological chemistry
The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 59 citations in OpenAlex.
- Spatial and functional characterization of ER stress proteins links fibroblast plasticity and proliferative processes in human osteoarthritic synovitis.Cell death and differentiation · 2026Article
- Elevated MANF expression in β cells protects mice from streptozotocin-induced diabetes by attenuating islet stress and immunogenicity.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Proteomic Analysis of Paired FFPE Tissue and Extracellular Vesicles Reveals Proteins Associated with Recurrence in Stage II Colorectal Cancer.Journal of proteome research · 2026Article
- Modulation of the unfolded protein response with a C-terminal fragment of MANF facilitates recovery in models of multiple sclerosis.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Neurotrophic Factors: Emerging Biology and Therapeutic Applications for Cardiovascular Diseases.Metabolites · 2026Review
- Spatial transcriptomics analysis uncovers ER stress in MANF-deficient Purkinje cells underlying alcohol-induced cerebellar neurodegeneration in mice.Acta neuropathologica communications · 2025Article
- Cerebral Dopamine Neurotrophic Factor (CDNF) Acts as a Trophic Factor Promoting Neuritogenesis in the Dorsal Root Ganglia (DRG) Neurons Through Activation of the PI3K Signaling Pathway.Journal of neurochemistry · 2025Article
- Investigation of the mesencephalic astrocyte-derived neurotrophic factor-endoplasmic reticulum stress pathway in mood disorders.The international journal of neuropsychopharmacology · 2025Article
- MANF facilitates breast cancer cell survival under glucose-starvation conditions via PRKN-mediated mitophagy regulation.Autophagy · 2025Article
- Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Mitigates Neuroinflammation and Cognitive Impairment by Modulating Glial Activation in Sepsis-Associated Encephalopathy.Neurochemical research · 2024Article
- The neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis inProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Increased expression of mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to synapse loss in Alzheimer's disease.Molecular neurodegeneration · 2024Article
- Structural basis of CDNF interaction with the UPR regulator GRP78.Nature communications · 2024Article
- MANF serves as a novel hepatocyte factor to promote liver regeneration after 2/3 partial hepatectomy via doubly targeting Wnt/β-catenin signaling.Cell death & disease · 2024Article
- Histone deacetylase inhibition expands cellular proteostasis repertoires to enhance neuronal stress resilience.bioRxiv : the preprint server for biology · 2024Article
- Machine learning and 4D-LFQ quantitative proteomic analysis explore the molecular mechanism of kidney stone formation.Heliyon · 2024Article
- The Essential Functions of Molecular Chaperones and Folding Enzymes in Maintaining Endoplasmic Reticulum Homeostasis.Journal of molecular biology · 2024Review
- MANF protein expression is upregulated in immune cells in the ischemic human brain and systemic recombinant MANF delivery in rat ischemic stroke model demonstrates anti-inflammatory effects.Acta neuropathologica communications · 2024Article
- Neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis inbioRxiv : the preprint server for biology · 2024Article
- Sex-specific effects of alcohol on neurobehavioral performance and endoplasmic reticulum stress: an analysis using neuron-specific MANF deficient mice.Frontiers in pharmacology · 2024Article
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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 naïve 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.
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