Cell reports最新文献

Astrocytes coordinate vascular homeostasis and tissue clearance in the brain, yet how these functions are mechanistically integrated remains unclear. Here, we identify neogenin (NEO1) as a cortex-specific astrocytic regulator that links angiogenesis with phagocytosis. Astrocyte-specific deletion of NEO1 in the mouse cortex, but not the hippocampus, leads to elevated HIF1/2α levels, increased expression of the angiogenic factor VEGFa, and reduced expression of the phagocytic receptor MEGF10. Mechanistically, loss of NEO1 induces intracellular iron deficiency, resulting in impaired prolyl hydroxylase-dependent degradation of HIF1/2α. This iron dysregulation is associated with reduced hepcidin expression and increased levels of the iron exporter ferroportin. Stabilized HIF1/2α preferentially engages HIF1β-p300 complexes at the VEGFa promoter to promote angiogenesis while reducing HIF1β-p300 occupancy at the MEGF10 promoter, thereby suppressing phagocytic gene expression. Together, these findings establish NEO1 as a critical cortical astrocytic regulator that balances vascular remodeling and phagocytic capacity through control of iron homeostasis and HIF-dependent transcription.

AIM2-like receptors (ALRs) are critical for host defense by sensing intracellular foreign DNA and aberrant self-DNA to activate inflammasomes. Here, we demonstrate that both human and mouse AIM2 undergo liquid-liquid phase separation (LLPS) upon binding dsDNA. Multivalent interactions within the OB1 and OB2 subdomains of the AIM2 HIN domain are essential for LLPS and subsequent inflammasome activation. In AIM2 knockout THP-1 cells, LLPS-deficient AIM2 mutants exhibit markedly impaired inflammasome activation and antiviral responses. ASC recruitment promotes the solidification of AIM2-dsDNA condensates. Notably, HIN domains from multiple ALRs, including human AIM2, human IFI16, mouse AIM2, and porcine MNDAL, form dsDNA-induced condensates, suggesting that HIN-domain-mediated LLPS is a conserved mechanism across the HIN-200 family. Finally, we identify the α-herpesvirus tegument protein VP22 as a viral antagonist that disrupts AIM2-dsDNA LLPS to evade AIM2 inflammasome activation. Collectively, these findings elucidate a unified LLPS-dependent mechanism for ALR-mediated DNA sensing and inflammasome activation and uncover a viral immune evasion strategy targeting biomolecular condensates.

Metabolites are key regulators of cell fate decisions, chromatin remodeling, and lineage commitment. While genetic pathways governing testis differentiation are well studied, the role of metabolism remains poorly understood. In this study, we investigate the transient, male-specific accumulation of glycogen in supporting cells of the fetal testis in mice, between embryonic days 11.5 and 13.5. Blocking glycogen metabolism/accumulation in vivo and in vitro is dispensable for Sertoli cell differentiation. However, its disruption leads to reduced lactate production and reduced germ cell number in the testis. Inhibiting lactate transport reveals a critical metabolic coupling between Sertoli and germ cells during early testis development. Surprisingly, external lactate or glucose supplementation fails to rescue the germ cell phenotype. These findings suggest that glycogen accumulation supports a critical developmental window in which both Sertoli and germ cells are metabolically constrained and unable to rely on external carbon sources.

The anti-inflammatory properties of granulocytic myeloid-derived suppressor cells (G-MDSCs) promote Staphylococcus aureus (S. aureus) biofilm persistence. Evidence suggests that G-MDSC activity is shaped not only by S. aureus products but also by intrinsic metabolic programs. This study explores whether G-MDSC activity can be modulated by increasing mitochondrial abundance using a co-culture paradigm with macrophages as a mitochondrial donor. Macrophages transfer mitochondria directly to G-MDSCs via tunneling nanotubes, enhancing G-MDSC respiration, as reflected by increased basal, maximal, and spare respiratory capacity. Augmenting mitochondrial abundance in G-MDSCs enhances T cell-suppressive activity and reduces tumor necrosis factor (TNF) and interleukin 6 (IL-6) production. In a mouse model of S. aureus prosthetic joint infection, adoptively transferred macrophages deliver mitochondria to G-MDSCs, enhancing their suppressive activity and increasing bacterial burden, which is reversed when macrophages with non-functional mitochondria are introduced. These findings support the theory that G-MDSCs exploit mitochondria to augment their anti-inflammatory properties in response to S. aureus biofilm.

Genome-scale targeted CRISPR libraries for forward genetic screens in plants are powerful tools for functional analysis, but they suffer from limited spatial control, single sgRNA design, and poor handling of genetic redundancy. We develop multiplexed CRISPR libraries in which each construct contains two sgRNAs that simultaneously target multiple members of a gene family. The libraries can also function at the cell-type-specific and tissue levels. A double-barcoding strategy enables efficient tracking and identification of sgRNA combinations at the plant level without individually sequencing each line. Using this platform, we generate over 1,000 Arabidopsis lines that express sgRNAs targeting 707 transporter genes across 114 gene families involved in nutrient uptake. The multiplexed design increases gene coverage and editing efficiency, underscoring its improved targeting capability to reveal hidden phenotypes. This toolbox provides a scalable resource for multi-targeted genome editing and spatially precise forward genetic screens in plants.

Endogenous (self) double-stranded RNAs (dsRNAs) in human cells can activate innate immune responses. ADAR1, an A-to-I editing enzyme of dsRNAs, suppresses aberrant immune activation by self-dsRNAs. However, how ADAR1 influences the cellular dsRNA landscape remains unclear. We show that human ADAR1 downregulates self-dsRNA abundance through editing-dependent and editing-independent mechanisms. We further conducted quantitative dsRNA sequencing on wild-type and ADAR1-deficient cells. dsRNAs are enriched in protein-coding mRNAs-especially those with repetitive elements and elongated 3' UTRs-and mitochondrial RNAs. ADAR1-regulated dsRNA transcripts consist of nuclear-encoded mRNAs and, unexpectedly, mitochondria-encoded RNAs rarely edited by ADAR1. Accordingly, dsRNAs accumulate to high levels within the mitochondria of ADAR1-deficient cells. Mass spectrometry and biochemical assays can detect ADAR1p150 in mitochondrial fractions. Notably, ADAR1 loss sensitizes cells to inflammation under mitochondrial stress (e.g., herniation and X-ray irradiation). Hence, we show that dsRNAs regulated by ADAR1 go beyond A-to-I edited transcripts and that ADAR1 can control mitochondrial dsRNAs.

The first exposure to a pathogen impacts subsequent immune responses toward related pathogens. This immune imprinting explains that infection or vaccination with circulating SARS-CoV-2 variants primarily recalls cross-reactive memory B cells induced by prior Wuhan-Hu-1 (Wu) spike (S) exposure. The magnitude and persistence of immune imprinting in mRNA vaccinees are not understood. We investigate serum antibody and memory B cell responses after administration of multiple XBB.1.5 and JN.1/KP.2 COVID-19 vaccine boosters. We find that the JN.1/KP.2 booster elicits broadly neutralizing antibody responses against recent SARS-CoV-2 variants by recalling Wu S-induced immunity in all but one individual. We detect an increased fraction of serum antibodies, and particularly memory B cells, recognizing XBB.1.5 and KP.2, but not Wu, relative to individuals who received a single XBB.1.5 booster. Repeated exposures to antigenically divergent S thus contribute to overcoming immune imprinting and support vaccine updates for continued protection.