Disentangaling the gene expression programs controlled by ciliary and cytosolic cAMP signaling
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ABSTRACT:
PROVIDER: PRJNA755958 | ENA |
REPOSITORIES: ENA
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Project description:Primary cilia are tiny membrane protrusions emanating from the surface of almost all mammalian cell types. Recently, a picture has emerged of the primary cilium functioning as a cellular antenna that senses extracellular stimuli via receptors, locally processes the signal using cilia-specific signalling pathways, and transduces this information into a cellular response. Components of the cyclic AMP (cAMP) signalling cascade have been proposed to be part of the ciliary signalling pathways. We aimed to shed light on whether ciliary cAMP signaling controls gene expression, and if yes, which gene expression program is particularly targeted by ciliary cAMP signaling. To this end, we targeted an optogenetic tool to increase cAMP levels (bPAC) to the primary cilium in murine, kidney-derived inner medullary collecting duct (mIMCD-3) cells (mIMCD-3 cilia-bPAC cells). As controls, we used cells were bPAC is targeted to the cytosol (mIMCD-3 cyto-bPAC cells) and wild-type cells (mIMCD-3 WT cells). We increased cAMP levels by light stimulation and next analysed gene expression using bulk RNA-sequencing. As an additional control, we also included WT cells treated with the compound Forskolin, which targets endogeneous adenylyl cyclases and thus, in principle, is believed to increase cAMP levels in both compartments, cilium and cell soma.
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Project description:Cilia and flagella are dynamicallyregulatedduring development and differentiation. Coordination of temporal and spatial transcription regulators are essential for ciliogenesis. We here report that XAP5 and XAP5L are two conserved pairs of antagonistic transcription regulators that control ciliary transcriptional programs during spermatogenesis. Male mice lacking either XAP5 or XAP5L display infertility, as a result of meiotic prophase arrest and sperm cilia malformation, respectively. XAP5 positively regulates the ciliary gene expression by activating the key regulators including FOXJ1 and RFX families during the early stage of spermatogenesis. In contrast, XAP5L negatively regulates the expression of ciliary genes via repressing these ciliary transcription factors during the spermiogenesis stage. Taken together, our data provide new insights into the mechanisms by which temporal and spatial transcription regulators are coordinated to control ciliary transcriptional programs during spermatogenesis.
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Project description:Axonemal dynein motors drive ciliary motility and can consist of up to twenty distinct components with a combined mass of ~2 MDa. In mammals, failure of dyneins to assemble within the axonemal superstructure leads to primary ciliary dyskinesia. Syndromic phenotypes include infertility, rhinitis, severe bronchial conditions, and situs inversus. Nineteen specific cytosolic factors (DNAAFs) are necessary for axonemal dynein assembly although the detailed mechanisms involved remain very unclear. Here we identify the assembly factor DNAAF3 as a structural ortholog of S-adenosyl methionine-dependent methyltransferases. We further demonstrate that dynein heavy chains, especially those forming the ciliary outer arms, are methylated on key residues within various nucleotide-binding sites and on microtubule-binding domain helices directly involved in the transition to low binding affinity. These variable modifications, which are generally missing in a Chlamydomonas null mutant for the DNAAF3 ortholog PF22 (DAB1), likely impact on motor mechanochemistry fine-tuning the activities of individual dynein complexes.
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Project description:The primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein-coupled receptor GPR161 in response to Hedgehog; and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the phosphatase Paladin as a cell type-specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.
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Project description:The primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein-coupled receptor GPR161 in response to Hedgehog; and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the phosphatase Paladin as a cell type-specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.
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Project description:The primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein-coupled receptor GPR161 in response to Hedgehog; and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the phosphatase Paladin as a cell type-specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.
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Project description:EPAC1, a cAMP-activated GEF for Rap GTPases, is a major transducer of cAMP signaling in normal cells and a therapeutic target in cardiac diseases. The recent discovery that cAMP is compartmentalized in membrane-proximal nanodomains challenged the current model of EPAC1 activation in the cytosol. Here, we discover that anionic membranes are a major component of EPAC1 activation. We find that anionic membranes activate EPAC1 in the absence of cAMP, that they increase its affinity for cAMP by 2 orders of magnitude, and that they synergize with cAMP to yield maximal GEF activity. Thus, EPAC1 has four states that differ in their affinity for cAMP and GEF efficiency. In cells, where cytosolic cAMP is low, this implies that EPAC1 must be primed by membranes to bind cAMP. Examination of the inhibitory mechanism of the cardiomyocyte-active chemical CE3F4 in this new framework further reveals that it targets only only membrane- and cAMP-activated EPAC1. Together, our findings reformulate previous concepts of cAMP signaling to include a hitherto overlooked role of membranes through EPAC proteins, with important implications for drug discovery.
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Project description:Oxidative phosphorylation (OXPHOS) is fundamental for life. OXPHOS complexes pose a unique challenge for the cell, because their subunits are encoded on two different genomes, the nuclear genome and the mitochondrial genome. Genomic approaches designed to study nuclear/cytosolic and bacterial gene expression have not been broadly applied to the mitochondrial system, thus the co-regulation of OXPHOS genes remains largely unexplored. Here we globally monitored mitochondrial and nuclear gene expression processes during mitochondrial biogenesis when OXPHOS complexes are synthesized. Nuclear- and mitochondrial- encoded OXPHOS transcript levels do not increase concordantly. Instead, we observe that mitochondrial and cytosolic translation are rapidly and dynamically regulated in a strikingly synchronous fashion. Furthermore, the coordinated translation programs are controlled unidirectionally through the intricate and dynamic control of cytosolic translation. Thus the nuclear genome carefully directs the coordination of mitochondrial and cytosolic translation to orchestrate the timely synthesis of each OXPHOS complex, representing an unappreciated regulatory layer shaping the mitochondrial proteome. Our whole-cell genomic profiling approach establishes a foundation for global gene regulatory studies of mitochondrial biology.
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