EMBO Reports最新文献

Mitochondrial DNA (mtDNA) serves as a potent activator for cellular innate immune responses. Topoisomerase 3α (TOP3α), a type IA topoisomerase, is canonically localized to mitochondria and nuclei, but its enigmatic cytosolic fraction-observed over two decades ago-has remained functionally undefined. Here, we uncover a critical role for cytosolic TOP3α in amplifying mtDNA-triggered innate immunity. We observe that aberrant TOP3α expression causes mtDNA clustering and release via mPTP-VDAC, stimulating cGAS-mediated inflammatory responses. Cytosolic TOP3α facilitates the sensing of released mtDNA by cGAS and amplifies downstream innate immune signaling. Using an in vitro cell-free system, we reveal that TOP3α directly augments mtDNA interaction with cGAS, which in turn competes with TOP3α for mtDNA binding. A rare mutation of a highly conserved residue (G250D) of TOP3α impairs the assembly of TOP3α polypeptides into protein complexes and its binding to mtDNA. Furthermore, mutant TOP3α hinders cGAS-mtDNA interaction and compromises cGAS-driven immunity. Our findings reveal a function for cytosolic TOP3α as a regulator for cGAS-driven inflammation.

The microbiome is increasingly recognized as playing a critical role in lung cancer prevention, diagnosis, and treatment. While bacteria are essential for tumor angiogenesis, the impact of fungi on this process remains largely unexplored. In this study, we investigate effects of Aspergillus fumigatus (A. fumigatus) on lung cancer. We show that inhalation of A. fumigatus increases tumor burden and angiogenesis in mouse models. Interestingly, A. fumigatus does not directly affect the proangiogenic abilities of tumor cells or endothelial cells. Instead, A. fumigatus promotes the accumulation of myeloid-derived suppressor cells (MDSCs), particularly G-MDSCs, in tumor tissues. A. fumigatus increases VEGF-A secretion from tumor-associated MDSCs, promoting tumor angiogenesis. Furthermore, we identify solute carrier family 7 member 11 (SLC7A11) as a key player in regulating this proangiogenic function through an interaction with High Mobility Group Box 1 (HMGB1) in MDSCs. Our results shed light on the mechanisms by which A. fumigatus influences MDSCs to promote angiogenesis and demonstrate that commensal fungi influence host immunity and support tumor progression.

Chromosome segregation errors in human oocytes increase dramatically as women age and premature loss of meiotic cohesion is one factor that contributes to a higher incidence of segregation errors in older oocytes. Here we show that knockdown of the NAD⁺-dependent deacetylase Sirt1 during meiotic prophase in Drosophila oocytes causes premature loss of arm cohesion and chromosome segregation errors. We demonstrate that acetylation of the Sirt1 substrate H4K16 increases significantly in sirt1 null and Sirt1 knockdown oocytes and use this as a marker for Sirt1 activity in vivo. When oocytes undergo aging, the H4K16ac signal increases significantly, consistent with an aging-dependent decline in Sirt1 deacetylase activity. However, if females are fed the Sirt1 activator SRT1720 as their oocytes age, the H4K16ac signal on oocyte DNA remains low in aged oocytes, consistent with preservation of Sirt1 activity during aging. Strikingly, age-dependent segregation errors are significantly reduced if mothers are fed SRT1720 while their oocytes age. Our data suggest that maintaining Sirt1 activity in aging oocytes may provide a viable therapeutic strategy to decrease age-dependent segregation errors.

Most eukaryotes share core meiosis-specific genes, suggesting meiosis evolved once in the last eukaryotic common ancestor (LECA). These genes are master regulators of meiotic recombination, ensuring genetically diverse lineages. However, meiosis in organisms outside the animal, plant, and yeast lineages remains poorly understood. Core meiotic genes were recently identified in the model brown alga Ectocarpus but remain uncharacterised. Here, we combine bioinformatic, structural, and biochemical approaches to characterise the axial-element orthologues meiotic Ectocarpus HORMA-domain protein (ecHOP1) and its interactor reductional division protein 1 (ecRED1), providing insight into meiotic-recombination regulation in brown algae. We define the chromatin-binding region of ecHOP1 and show that it binds double-stranded DNA, and we find that Ectocarpus assembles its axial element using evolutionarily conserved principles in a unique combination. Our work lays a foundation for further studies of meiosis in brown algae and broadens understanding of the diversity and conservation of meiotic mechanisms.

Telomeres are essential for chromosome protection and genomic stability, and telomerase function is critical for organ homeostasis. Zebrafish is a useful vertebrate model for understanding cellular and molecular mechanisms of regeneration. The regeneration capacity of the caudal fin of wild-type zebrafish is not affected by repetitive amputation, but the behaviour of telomeres during this process has not yet been studied. Here, we characterize the regeneration process in a telomerase-deficient zebrafish model, and study the regenerative capacity after repetitive amputations at different ages. We find that the regenerative efficiency decreases with aging in all genotypes but telomere length is maintained even in telomerase-deficient fish. Our data indicate that telomere length can be maintained by the regenerating cells through the recombination-mediated Alternative Lengthening of Telomeres (ALT) pathway, which likely supports high rates of cell proliferation during the caudal fin regeneration process.

Naïve human embryonic stem cells (hESCs) possess some advantages over their primed counterparts, displaying distinctive metabolic and epigenetic properties. However, the master regulator governing these features remains unrecognized. Here, we systematically investigate functions of the core transcription factor NANOG in naïve hESCs. Acting as an upstream key regulator, NANOG directly activates genes associated with naïve pluripotency, acetyl-CoA synthesis and anti-oxidation in a naïve pluripotency state- dependent manner, and represses the expression of extraembryonic lineage genes in naïve hESCs. NANOG modulates transcription of multiple genes in various pathways of acetyl-CoA synthesis, maintains the intracellular acetyl-CoA level and characteristic epigenetic landscapes, particularly the high level of histone acetylation, in naïve hESCs. NANOG is indispensable for the high activity of both OXPHOS and glycolysis, a bivalent metabolic state typical in naïve hESCs. Furthermore, we identify GPX2 as a mediator of NANOG in sustaining redox balance and survival of naïve hESCs. Together, this study reveals previously unrecognized roles of NANOG in orchestrating transcriptional, metabolic and epigenetic signatures to secure human naïve pluripotency.

Batten disease is characterized by early-onset blindness, juvenile dementia and death within the second decade of life. The most common genetic cause are mutations in CLN3, encoding a lysosomal protein. Currently, no therapies targeting disease progression are available, largely because its molecular mechanisms remain poorly understood. To understand how CLN3 loss affects cellular signaling, we generated human CLN3 knock-out cells (CLN3-KO) and performed RNA-seq analysis. Our multi-dimensional analysis reveals the transcriptional regulator YAP1 as a key factor in remodeling the transcriptome in CLN3-KO cells. YAP1-mediated pro-apoptotic signaling is also increased as a consequence of CLN3 functional loss in retinal pigment epithelia cells, and in the hippocampus and thalamus of Cln3^Δ7/8 mice, an established model of Batten disease. Loss of CLN3 leads to DNA damage, activating the kinase c-Abl which phosphorylates YAP1, stimulating its pro-apoptotic signaling. This novel molecular mechanism underlying the loss of CLN3 in mammalian cells and tissues may pave a way for novel c-Abl-centric therapeutic strategies to target Batten disease.

Sexual dimorphism in neural wiring and behavior arises from both intrinsic genetic programs and environmental cues, yet how these factors interact to shape neuronal morphogenesis remains unclear. Here, we investigate sexually dimorphic collateral branching in PVP cholinergic interneurons of Caenorhabditis elegans. In hermaphrodites, PVP branches form near the vulva and exhibit dynamic morphologies enriched with synaptic proteins for dense core vesicles but not synaptic vesicles, suggesting a role in selective neuropeptide transmission. We find that sex identity is necessary but not sufficient for PVP branching. Sex identity engages autonomous insulin signaling via the FOXO transcription factor DAF-16 to promote branch formation and modulate dynamic branch morphologies according to nutritional status. However, external epithelial cues from primary vulval cells are both necessary and sufficient to induce branching independent of sex identity. Despite acting through distinct pathways, insulin signaling and vulval cues converge on F-actin cytoskeletal remodeling. These sexually dimorphic PVP branches modulate egg-laying behavior in hermaphrodites. Our study uncovers a multilayered regulatory framework integrating intrinsic sex-specific programs and extrinsic signaling to shape sexually dimorphic neural circuits.

Secretin is a gastrointestinal (GI) hormone that slows intestinal motility, an effect thought to be mediated through vagal afferent pathways. In this study we show evidence for a novel function of secretin involving a non-neural mechanism mediated by interstitial cells of Cajal (ICC). Transcripts of secretin receptors (Sctr) are expressed abundantly by ICC in the deep muscular plexus (ICC-DMP). Secretin inhibits small intestinal contractions in the presence of the neurotoxin, tetrodotoxin (TTX) and suppresses excitatory enteric neurotransmission. The inhibitory effects of secretin occur through inhibition of Ca²⁺ transients in ICC-DMP, likely via Gαs-coupled cAMP production and PKA activation that leads to inhibition of IP3 receptors. Our results provide a novel concept for the role of ICC-DMP in small intestinal motility. ICC-DMP serve as integration hubs in which signaling from the enteric nervous system and hormones converge and integrate regulatory responses controlling intestinal motility. In the case of secretin, integrated responses may serve to slow intestinal transit to enhance digestion and absorption of nutrients.

Early embryos often have unique chromatin states prior to zygotic genome activation (ZGA). In Drosophila, ZGA occurs after 13 reductive nuclear divisions during which the nuclear to cytoplasmic (N/C) ratio grows exponentially. Previous work found that histone H3 chromatin incorporation decreases while its variant H3.3 increases leading up to ZGA. In other cell types, H3.3 is associated with sites of active transcription and heterochromatin, suggesting a link between H3.3 and ZGA. Here, we test what factors regulate H3.3 incorporation at ZGA. We find that H3 nuclear availability falls more rapidly than H3.3 leading up to ZGA. We generate H3/H3.3 chimeric proteins at the endogenous H3.3 A locus and observe that chaperone binding, but not gene structure, regulates H3.3 behavior. We identify the N/C ratio as a major determinant of H3.3 incorporation. To isolate how the N/C ratio regulates H3.3 incorporation we test the roles of genomic content, zygotic transcription, and cell cycle state. We determine that cell cycle regulation, but not H3 availability or transcription, controls H3.3 incorporation. Overall, we propose that local N/C ratios control histone variant usage via cell cycle state during ZGA.