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Mesencephalic astrocyte-derived neurotrophic factor is involved in inflammation by negatively regulating the NF-κB pathway.

ABSTRACT: Inflammation can cause endoplasmic reticulum (ER) stress and therefore activates the unfolded protein response (UPR). ER stress and the consequent UPR have the potential to activate NF-κB. However, the factors mediating the crosstalk between ER stress and the NF-κB pathway remain unclear. Here, we determined that ER stress inducible protein Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) was up-regulated in autoimmune diseases and inflammatory disease models. Inflammation caused MANF to relocalize to the nuclei. MANF interacted with the DNA binding domain of p65 through its C-terminal SAP-like domain in the nuclei under the condition of inflammation or ER stress. MANF consequently inhibited p65-mediated transcriptional activation by interfering with the binding of p65 to its target genes promoters. Consistently, MANF suppressed the expressions of NF-κB-dependent target genes and the proliferation of inflammatory synoviocytes. These findings suggest that MANF may be a negative regulator of inflammation and mediate the crosstalk between the NF-κB pathway and ER stress.

SUBMITTER: Chen L

PROVIDER: S-EPMC4313098 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Mesencephalic astrocyte-derived neurotrophic factor is involved in inflammation by negatively regulating the NF-κB pathway.

Chen Lijian L Feng Lijie L Wang Xia X Du Jian J Chen Ying Y Yang Wen W Zhou Chengyue C Cheng Li L Shen Yujun Y Fang Shengyun S Li Jun J Shen Yuxian Y

Scientific reports 20150202

Inflammation can cause endoplasmic reticulum (ER) stress and therefore activates the unfolded protein response (UPR). ER stress and the consequent UPR have the potential to activate NF-κB. However, the factors mediating the crosstalk between ER stress and the NF-κB pathway remain unclear. Here, we determined that ER stress inducible protein Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) was up-regulated in autoimmune diseases and inflammatory disease models. Inflammation caused MANF ...[more]

PMID: 25640174

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Project description:Background and aimsEndoplasmic reticulum (ER) stress is associated with liver inflammation and hepatocellular carcinoma (HCC). However, how ER stress links inflammation and HCC remains obscure. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-inducible secretion protein that inhibits inflammation by interacting with the key subunit of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) p65. We hypothesized that MANF may play a key role in linking ER stress and inflammation in HCC.Approach and resultsHere, we found that MANF mRNA and protein levels were lower in HCC tissues versus adjacent noncancer tissues. Patients with high levels of MANF had better relapse-free survival and overall survival rates than those with low levels. MANF levels were also associated with the status of liver cirrhosis, advanced tumor-node-metastasis (TNM) stage, and tumor size. In vitro experiments revealed that MANF suppressed the migration and invasion of hepatoma cells. Hepatocyte-specific deletion of MANF accelerated N-nitrosodiethylamine (DEN)-induced HCC by up-regulating Snail1+2 levels and promoting epithelial-mesenchymal transition (EMT). MANF appeared in the nuclei and was colocalized with p65 in HCC tissues and in tumor necrosis factor alpha (TNF-α)-treated hepatoma cells. The interaction of p65 and MANF was also confirmed by coimmunoprecipitation experiments. Consistently, knockdown of MANF up-regulated NF-κB downstream target genes TNF-α, interleukin (IL)-6 and IL-1α expression in vitro and in vivo. Finally, small ubiquitin-related modifier 1 (SUMO1) promoted MANF nuclear translocation and enhanced the interaction of MANF and p65. Mutation of p65 motifs for SUMOylation abolished the interaction of p65 and MANF.ConclusionsMANF plays an important role in linking ER stress and liver inflammation by inhibiting the NF-κB/Snail signal pathway in EMT and HCC progression. Therefore, MANF may be a cancer suppressor and a potential therapeutic target for HCC.

Project description:Alcohol exposure has detrimental effects on both the developing and mature brain. Endoplasmic reticulum (ER) stress is one of the mechanisms that contributes to alcohol-induced neuronal damages. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-responsive protein and is neuroprotective in multiple neuronal injury and neurodegenerative disease models. MANF deficiency has been shown to exacerbate alcohol-induced ER stress and neurodegeneration. However, it is unknown whether MANF supplement is sufficient to protect against alcohol neurotoxicity. Alcohol alters MANF expression in the brain, but the mechanisms underlying alcohol modulation of MANF expression remain unclear. This study was designed to determine how alcohol alters MANF expression in neuronal cells and whether exogeneous MANF can alleviate alcohol neurotoxicity. We showed that alcohol increased MANF transcription and secretion without affecting MANF mRNA stability and protein degradation. ER stress was necessary for alcohol-induced MANF upregulation, as pharmacological inhibition of ER stress by 4-PBA diminished alcohol-induced MANF expression. In addition, the presence of ER stress response element II (ERSE-II) was required for alcohol-stimulated MANF transcription. Mutations or deletion of this sequence abolished alcohol-regulated transcriptional activity. We generated MANF knockout (KO) neuronal cells using CRISPR/Cas9. MANF KO cells exhibited increased unfolded protein response (UPR) and were more susceptible to alcohol-induced cell death. On the other hand, MANF upregulation by the addition of recombinant MANF protein or adenovirus gene transduction protected neuronal cells against alcohol-induced cell death. Further studies using early postnatal mouse pups demonstrated that enhanced MANF expression in the brain by intracerebroventricular (ICV) injection of MANF adeno-associated viruses ameliorated alcohol-induced cell death. Thus, alcohol increased MANF expression through inducing ER stress, which could be a protective response. Exogenous MANF was able to protect against alcohol-induced neurodegeneration.

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Mesencephalic astrocyte-derived neurotrophic factor is involved in inflammation by negatively regulating the NF-κB pathway.

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Mesencephalic astrocyte-derived neurotrophic factor is involved in inflammation by negatively regulating the NF-κB pathway.

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