47 research outputs found
Oscillatory cAMP signaling rapidly alters H3K4 methylation
receptors (GPCRs) alter H3K4 methylation via oscillatory intracellular cAMP. Activation of Gs-coupled receptors caused a rapid decrease of H3K4me3 by elevating cAMP, whereas stimulation of Gi-coupled receptors increased H3K4me3 by diminishing cAMP. H3K4me3 gradually recovered towards baseline levels after the removal of GPCR ligands, indicating that H3K4me3 oscillates in tandem with GPCR activation. cAMP increased intracellular labile Fe(II), the cofactor for histone demethylases, through a non-canonical cAMP targetâRap guanine nucleotide exchange factor-2 (RapGEF2), which subsequently enhanced endosome acidification and Fe(II) release from the endosome via vacuolar H+-ATPase assembly. Removing Fe(III) from the media blocked intracellular Fe(II) elevation after stimulation of Gs-coupled receptors. Iron chelators and inhibition of KDM5 demethylases abolished cAMP-mediated H3K4me3 demethylation. Taken together, these results suggest a novel function of cAMP signaling in modulating histone demethylation through labile Fe(II)
Manganese causes neurotoxic iron accumulation via translational repression of Amyloid Precursor Protein (APP) and H-Ferritin
For more than 150 years, it is known that occupational overexposure of manganese (Mn) causes movement disorders resembling Parkinson's disease (PD) and PDâlike syndromes. However, the mechanisms of Mn toxicity are still poorly understood. Here, we demonstrate that Mn doseâ and timeâdependently blocks the protein translation of amyloid precursor protein (APP) and heavyâchain Ferritin (HâFerritin), both iron homeostatic proteins with neuroprotective features. APP and HâFerritin are postâtranscriptionally regulated by iron responsive proteins, which bind to homologous iron responsive elements (IREs) located in the 5âČâuntranslated regions (5âČâUTRs) within their mRNA transcripts. Using reporter assays, we demonstrate that Mn exposure repressed the 5âČâUTRâactivity of APP and HâFerritin, presumably via increased iron responsive proteinsâiron responsive elements binding, ultimately blocking their protein translation. Using two specific Fe2+âspecific probes (RhoNoxâ1 and IPâ1) and ion chromatography inductively coupled plasma mass spectrometry (ICâICPâMS), we show that loss of the protective axis of APP and HâFerritin resulted in unchecked accumulation of redoxâactive ferrous iron (Fe2+) fueling neurotoxic oxidative stress. Enforced APP expression partially attenuated Mnâinduced generation of cellular and lipid reactive oxygen species and neurotoxicity. Lastly, we could validate the Mnâmediated suppression of APP and HâFerritin in two rodent in vivo models (C57BL6/N mice and RjHan:SD rats) mimicking acute and chronic Mn exposure. Together, these results suggest that Mnâinduced neurotoxicity is partly attributable to the translational inhibition of APP and HâFerritin resulting in impaired iron metabolism and exacerbated neurotoxic oxidative stress
Siderophore-Mediated Zinc Acquisition Enhances Enterobacterial Colonization of the Inflamed Gut
Zinc is an essential cofactor for bacterial metabolism, and many Enterobacteriaceae express the zinc transporters ZnuABC and ZupT to acquire this metal in the host. However, the probiotic bacterium Escherichia coli Nissle 1917 (or âNissleâ) exhibits appreciable growth in zinc-limited media even when these transporters are deleted. Here, we show that Nissle utilizes the siderophore yersiniabactin as a zincophore, enabling Nissle to grow in zinc-limited media, to tolerate calprotectin-mediated zinc sequestration, and to thrive in the inflamed gut. We also show that yersiniabactinâs affinity for iron or zinc changes in a pH-dependent manner, with increased relative zinc binding as the pH increases. Thus, our results indicate that siderophore metal affinity can be influenced by the local environment and reveal a mechanism of zinc acquisition available to commensal and pathogenic Enterobacteriaceae
A Taxonomically-informed Mass Spectrometry Search Tool for Microbial Metabolomics Data
MicrobeMASST, a taxonomically-informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbial-derived metabolites and relative producers, without a priori knowledge, will vastly enhance the understanding of microorganismsâ role in ecology and human health
Recognition- and Reactivity-Based Fluorescent Probes for Studying Transition Metal Signaling in Living Systems
An Endoperoxide Reactivity-Based FRET Probe for Ratiometric Fluorescence Imaging of Labile Iron Pools in Living Cells
Recommended from our members
Activity-based sensing fluorescent probes for iron in biological systems.
Iron is an essential nutrient for life, and its capacity to cycle between different oxidation states is required for processes spanning oxygen transport and respiration to nucleotide synthesis and epigenetic regulation. However, this same redox ability also makes iron, if not regulated properly, a potentially dangerous toxin that can trigger oxidative stress and damage. New methods that enable monitoring of iron in living biological systems, particularly in labile Fe2+ forms, can help identify its contributions to physiology, aging, and disease. In this review, we summarize recent developments in activity-based sensing (ABS) probes for fluorescence Fe2+ detection
Recommended from our members
Activity-based sensing fluorescent probes for iron in biological systems.
Iron is an essential nutrient for life, and its capacity to cycle between different oxidation states is required for processes spanning oxygen transport and respiration to nucleotide synthesis and epigenetic regulation. However, this same redox ability also makes iron, if not regulated properly, a potentially dangerous toxin that can trigger oxidative stress and damage. New methods that enable monitoring of iron in living biological systems, particularly in labile Fe2+ forms, can help identify its contributions to physiology, aging, and disease. In this review, we summarize recent developments in activity-based sensing (ABS) probes for fluorescence Fe2+ detection