Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) protein that can be secreted and protects dopamine neurons and cardiomyocytes from ER stress and apoptosis. The mechanism of action of extracellular MANF has long been elusive. From a genetic screen for mutants with abnormal ER stress response, we identified the gene Y54G2A.23 as the evolutionarily conserved C. elegans MANF orthologue. We find that MANF binds to the lipid sulfatide, also known as 3-O-sulfogalactosylceramide present in serum and outer-cell membrane leaflets, directly in isolated forms and in reconstituted lipid micelles. Sulfatide binding promotes cellular MANF uptake and cytoprotection from hypoxia-induced cell death. Heightened ER stress responses of MANF-null C. elegans mutants and mammalian cells are alleviated by human MANF in a sulfatide-dependent manner. Our results demonstrate conserved roles of MANF in sulfatide binding and ER stress response, supporting sulfatide as a long-sought lipid mediator of MANF’s cytoprotection.
Highlights
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) protein that can be secreted and protects dopamine neurons and cardiomyocytes from ER stress and apoptosis
Our studies identify sulfatide as a lipid interactor of MANF and the sulfatide-binding capacity is critical for cytoprotective effects of MANF
We further demonstrate that sulfatide promotes cellular uptake of MANF in both C. elegans and mammalian cells and that C. elegans manf-1 mutants can be rescued by human MANF, suggesting highly evolutionarily conserved mechanisms by which MANF alleviates ER stress and cell toxicity under hypoxic and ER stress conditions
Summary
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) protein that can be secreted and protects dopamine neurons and cardiomyocytes from ER stress and apoptosis. Eukaryotic cells actively maintain protein folding and redox homeostasis in the ER upon hypoxic and oxidative stresses by regulating numerous cellular factors to promote normal physiological functions and cytoprotection. Among such factors that have been studied, mesencephalic astrocyte-derived neurotrophic factor (MANF) is an enigmatic family of proteins with rather unique mode and mechanisms of action. By characterizing C. elegans and human MANFs in lipid binding and roles in protecting from ER stress and cell death, we provide multiple lines of evidence that MANF confers cytoprotection, at least in part, through direct binding to sulfatide and subsequent uptake by both C. elegans and mammalian cells
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