Journal
SCIENTIFIC REPORTS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep08133
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Funding
- National Natural Science Foundation of China [81173074, 91129729, 81372576]
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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-kappa B. However, the factors mediating the crosstalk between ER stress and the NF-kappa B 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-kappa B-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-kappa B pathway and ER stress.
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