Cell reports最新文献

Immunoglobulin E (IgE)-dependent mast cell degranulation and anaphylaxis are suppressed by the CD300f-ceramide interaction. However, the related, positive regulatory mechanisms remain unclear. Here, we examine the effect of FcεRIγ-coupled CD300d3 on IgE-dependent anaphylaxis in mice. We identify sphingomyelin (SM) species as CD300d3 ligands, of which certain types bind CD300f. Stimulation with SM recognized by CD300d3, but not strongly by CD300f (referred to here as type I SM), promotes colocalization of SM-bound CD300d3 to the cross-linked high-affinity IgE receptor and enhances IgE-dependent mast cell degranulation. The IgE-dependent anaphylactic responses are consistently enhanced by type I SM. However, the same responses are attenuated by CD300d3 deficiency, by interfering with the SM-CD300d3 interaction, or by treatment with vesicles containing ceramide or SM recognized by both CD300d3 and CD300f (type II SM). Overall, mast cell- and IgE-dependent anaphylaxis in mice is regulated by the binding of specific sphingolipids present in tissues to activating CD300d3 versus inhibitory CD300f.

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths. Mutations in the tumor-suppressor APC initiate CRC in part by preventing the glycogen synthase kinase 3 (GSK3) kinase from phosphorylating β-CATENIN, leading to its stabilization and transactivation of mitogenic target genes. While the importance of β-CATENIN phosphorylation by GSK3 is well established, APC regulation of GSK3 activity upon other targets is not understood. Here, we identify the H4K20 methyltransferase SETD8 as a target of APC-coordinated GSK3 phosphorylation in the intestinal epithelium. We find that phosphorylation by GSK3 restrains the oncogenic activity of SETD8, with loss of phosphorylation sensitizing mice to oncogenic insults. Mechanistically, loss of SETD8 phosphorylation in tumors results in a loss of H4K20 monomethylation (H4K20me1) deposition at oncogenic cholesterol biosynthesis and fetal intestinal genes, allowing for their activation in part through gain of YAP accessibility. These results underscore the importance of SETD8 in CRC and represent a novel β-CATENIN-independent oncogenic consequence of APC loss.

G protein-coupled receptors (GPCRs) exhibit signaling bias or preferential activation of heterotrimeric G proteins versus GPCR kinase (GRK)-mediated β-arrestin signaling. The protease-activated receptor-1 (PAR1) activates both G protein and β-arrestin in response to thrombin but only β-arrestin in response to activated protein C (APC). Thrombin-activated PAR1-G protein signaling is desensitized by β-arrestin-1, whereas APC-activated PAR1 signaling is propagated by β-arrestin-2. The mechanisms underlying PAR1 biased signaling are not known. Here, using computational modeling combined with cellular and biochemical studies, we reveal the molecular basis of signaling by thrombin- and APC-activated PAR1. Although both thrombin- and APC-induced PAR1 signaling are regulated by the same GRK, GRK5, the two types of signaling are differentially dependent on GRK5 membrane anchoring, PAR1 C-terminal phosphorylation sites, and the binding mode of β-arrestin-2. These differences translate into distinct β-arrestin-2 conformations and define the APC cytoprotective signaling signature, which contrasts with thrombin inflammatory signaling.

Cancer cells rely on lipogenesis in addition to exogenous lipid uptake, and fatty acid synthase (FASN) is aberrantly overexpressed in myeloid leukemia, yet its role in leukemogenesis is unclear. We show that FASN is essential for leukemogenesis. Its genetic ablation impairs leukemic cell growth, survival, and clonogenicity in vitro, and reduces disease burden in vivo, without significantly affecting normal hematopoiesis. We further identify a platensimycin derivative compound MS-C19 as a potent FASN inhibitor. MS-C19 suppresses growth and clonogenicity in clinical acute myeloid leukemia (AML) samples. Mechanistically, FASN inhibition or deficiency activates lysosomal and inflammatory gene programs, inducing lysosomal membrane permeabilization and associated cell death but not lysosome biogenesis. We further identify that GRN, a lysosomal and neuroinflammatory gene, is potently transcribed by TFEB upon FASN inhibition. GRN depletion reverses the anti-leukemic effects of FASN loss. Our findings establish FASN as a therapeutic target and support its pharmacological inhibition by MS-C19 for leukemia treatment.

Yang et al. show that C. elegans embryos adapt to tetraploidy and maintain viability by scaling their transcriptome proportionately to their increased cell volume. Tetraploids display slower cell cycles and prolonged embryogenesis due to an elevated DNA-cell volume ratio.

Growth and defense are inversely correlated processes requiring balance for fitness. While each is well studied, its regulatory trade-offs are less understood. Using DANGEROUS MIX (DM) autoimmune plants with stunted growth in Arabidopsis thaliana, we investigate the balancing act. Transcriptome analysis of three DM cases and pathogen-treated seedlings identifies two major modules representing defense and growth. These core modules, comprising 4,712 genes (∼17% of the transcriptome), reveal consistent transcriptional antagonism across diverse immune datasets. Removing all three ADR1s, the helper nucleotide-binding leucine-rich repeats (NLRs), reverses the expression patterns of both modules and shifts the balance; ADR1s strongly affect growth-associated receptor-like kinase (RLK) genes more than defense genes. Autoimmune plants also show reciprocal chromatin accessibility changes, dominated by a widespread decrease at growth loci relative to sporadic increases at defense loci. Our findings suggest a mechanism where immune signaling, partly mediated by ADR1s, actively suppresses growth genes, providing a strategy to regulate the growth-defense trade-off.

Whole-organism polyploidy is widespread across species, yet how embryogenesis adapts to genome doubling remains unclear. Here, we present a systematic single-cell comparison of embryogenesis between de novo-induced tetraploid and diploid C. elegans embryos, integrating live imaging, lineage tracing, phenotypic quantification, and transcriptomic profiling. Despite elevated transcript levels, slower proliferation, and altered cell architecture, tetraploid embryos develop with high fidelity, producing cell numbers, lineage patterns, fate specification, and tissue morphogenesis virtually indistinguishable from diploids. In tetraploids, transcriptional output increases proportionally with cell volume, resulting in largely stable transcript concentrations, although specific gene sets show divergence, suggesting additional layers of regulation. The importance of this scaling is underscored by their heightened sensitivity to size perturbations. Meanwhile, a sublinear volume increase relative to genome content raises DNA-to-volume ratios, correlating with delayed proliferation, suggesting potential physical or regulatory constraints on volume expansion. Our findings reveal how intracellular scaling strategies support accurate embryogenesis following genome doubling.

Toxin-antitoxin-chaperone (TAC) systems are three-part gene clusters encoding a toxin, antitoxin, and specialized SecB-like chaperone (SecB^TA) with emerging roles in phage defense. To identify and classify SecB homologs and associated TACs across bacteria, we surveyed the full RefSeq database. Phylogenetic and gene neighborhood analyses reveal three major SecB subfamilies: two housekeeping groups and a diverse SecB^TA clade associated with eight TAC classes, five of which were previously unknown. Despite broad sequence divergence, structural predictions show conserved SecB tetrameric folds and toxin-antitoxin interfaces. The SecB chaperone phylogeny is incongruent with the identity of the TA component, suggesting modular shuffling during TAC evolution. We demonstrate toxicity of class 2 ART toxins from Escherichia coli, Bacillus subtilis, and Streptococcus gordonii, all of which we show inhibit protein synthesis. All TAC classes can be prophage encoded, indicative of phage-driven mobility and rapid diversification.

In cultivated soybean, the stepwise selection of genes controlling flowering time and maturity has been crucial for latitudinal adaptation and yield potential. Although the early flowering alleles of tof12 and tof11 are sequentially selected during domestication, they are insufficient to fully explain the genetic basis of adaptation to high-latitude environments. Here, we identify a locus, Dgt1 (Downstream Gene of Tof11 and Tof12), that regulates flowering time and latitude adaptation in soybean. We demonstrate that Dgt1 encodes a homolog of REVEILLE1 (GmRVE1). Mechanistically, Tof11 and Tof12 directly suppress GmRVE1 expression, which represses flowering dependent on the E1 gene. Population genetic analyses reveal that the stepwise selection of Tof12, Tof11, and GmRVE1 promotes early flowering and enables the expansion of soybean cultivation from its domestication center to high-latitude regions. Our study provides a genetic resource for breeding ultra-early maturing and high-yielding soybean varieties.

Glioblastoma (GBM) remains a lethal tumor, largely due to robust mechanisms that prevent effective induction of cell death. Ferroptosis, a form of iron-dependent cell death, is a promising vulnerability in GBM. Here, we demonstrate that lipocalin-2 (LCN2) suppresses ferroptosis in GBM cells via the receptor tyrosine kinase AXL. LCN2 was elevated in GBM cells compared to lower-grade tumor and non-transformed cells, and Lcn2 knockdown impaired GBM cell fitness and growth in vitro and in vivo. Mechanistically, Lcn2 knockdown triggered ferroptosis, which was specifically rescued with ferroptosis inhibitors but not apoptosis or necroptosis inhibitors. Lcn2 knockdown reduced AXL phosphorylation, which was elevated in GBM patient tumors relative to non-tumor tissue. Notably, the combination of Lcn2 knockdown and pharmacological AXL inhibition extended survival compared to Lcn2 knockdown alone. Taken together, these data reveal a link between LCN2-mediated suppression of ferroptosis with AXL phosphorylation and support this axis as a potential therapeutic target for GBM.