Cell reports最新文献

Chronic pain frequently co-occurs with depression, forming a vicious cycle that mutually exacerbates both. Although the medial shell of nucleus accumbens (NAcMed) is known to modulate both pain and affective states, the distinct roles of D1- and D2-dopamine receptor-expressing medium spiny neurons (D1- and D2-MSNs) within the NAcMed, as well as their respective circuits, in chronic pain and comorbid depression remain poorly defined. We observed decreased activity in both MSN subtypes during chronic pain and comorbid depression. Notably, activation of D1-MSNs alleviated depressive-like behaviors, whereas activation of D2-MSNs produced analgesic effects. Furthermore, we identified two parallel neural circuits: the NAcMed^D1-MSNs→mediodorsal thalamus pathway, which preferentially modulates depressive-like behaviors, and the NAcMed^D2-MSNs→lateral hypothalamus pathway, which selectively relieves pain. These findings delineate a circuit-specific dichotomy in which NAcMed^D1-MSNs and NAcMed^D2-MSNs govern distinct affective and sensory dimensions of chronic pain-depression comorbidity, providing circuit-specific targets for potential treatment.

The ETS family transcription factor ETV2, VEGFA, and its receptor FLK1 are essential for hematopoietic, vascular, and cardiac development. Here, we combine dual Etv2 and Flk1 lineage tracing with molecular profiling to define how mesoderm progenitors are allocated to hematopoietic, endothelial, cardiomyocyte, and smooth muscle lineages. We demonstrate that hematopoietic, endothelial, and cardiac valves arise from dual Etv2⁺ and Flk1⁺ lineages and that Etv2⁺ and Flk1⁺ mesoderm contributing to the hemangiogenic fate is molecularly distinct from that generating muscle. Mechanistically, we show that ETV2 cooperates with the BAF chromatin remodeling complex to establish accessibility at ETV2 target loci. Loss of Baf155 expression reduces chromatin accessibility at ETV2 target loci and impairs hemangiogenic lineage specification. This work defines lineage relationships and the molecular circuitry underlying hemangiogenic specification during cardiovascular development.

Genotype-dependent regeneration efficiency remains a major obstacle in wheat transformation, limiting its use in elite but recalcitrant cultivars. To elucidate the molecular basis of regeneration divergence, we compare transcriptomic profiles, chromatin accessibility dynamics, and transcriptional regulatory networks (TRNs) between the regenerable variety Fielder and the recalcitrant variety JiMai22 (JM22). Fielder displays dynamic transcriptional reprogramming and chromatin remodeling between 3 and 6 days after induction, activating morphogenic regulators such as TaSCR, TaWOX5, and TaLBD17. In contrast, JM22 shows limited chromatin changes and transcriptional stagnation, primarily inducing stress-responsive pathways. TRN analysis reveals a more complex, regeneration-focused network in Fielder, enriched with AP2, Dof, and GRAS transcription factor families. Among these, TaSCR is identified as a key regulator. Functional assays demonstrate that the TaSCR-TaLBD17 regulatory cascade improves transformation efficiency across diverse wheat genotypes. These findings provide a molecular framework to overcome transformation barriers in recalcitrant cultivars.

Homeostasis of the nervous system is maintained by a population of resident neural stem cells (NSCs) retained in a state of reversible cell-cycle arrest called quiescence. Quiescent NSCs can resume proliferation in response to different physiological stimuli. Reactivation requires changes in gene expression, much of which is regulated at the epigenomic level. We mapped epigenomic changes in NSC chromatin during stem cell quiescence and reactivation in Drosophila in vivo. Contrary to expectations, chromatin accessibility is increased in quiescent NSCs. Surprisingly, genes crucial for cell-cycle progression are repressed while remaining within permissive H3K36me3-bound euchromatin. At the same time, genes necessary for cell-cell communication are derepressed by eviction of histone H1 and transition to an SWI/SNF-enriched active state. Our results reveal global expansion of accessible chromatin in quiescent NSCs without concomitant transcriptional activation. Strikingly, this process reverses upon reactivation, indicating that opening of chromatin is a quiescence-specific event.

Viral protein genome-linked (VPg) is a small protein encoded by several non-enveloped positive-sense RNA viruses, including Cardiovirus. Although VPg is widely recognized as essential for viral RNA synthesis, its additional roles remain largely unexplored. Here, we report an alternative function of Cardiovirus VPg as an interferon-γ receptor agonist. During encephalomyocarditis virus (EMCV) infection, a member of the Cardiovirus genus, we uncovered that VPg from EMCV (VPg^EMCV) is released extracellularly from host cells. VPg^EMCV is then sensed by uninfected host cells, activating the interferon-γ signaling cascade and ultimately producing nitric oxide (NO) through inducible NO synthase induction. NO accumulation is crucial for triggering potent cell death in cooperation with tumor necrosis factor α (TNF-α) signaling, with TNF-α also being induced as an antiviral host response during EMCV infection. We demonstrate that VPg^EMCV, comprising merely 20 amino acids, can exhibit cytokine-mimicry activity, with the synergistic interplay between VPg^EMCV and TNF-α signaling regulating viral replication and disease pathogenesis.

Proteins are the most abundant source of amino acids in body fluids. However, the potential contribution of extracellular protein catabolism to the regulation of T cell immunity remains poorly understood. In this study, we show that endocytosed extracellular proteins function as an amino acid source in activated T cells, maintaining mTORC1 activity and sustaining cytokine production following T cell activation. Genetic ablation of Tfe3 impairs the activation-induced upregulation of lysosomal genes and disrupts extracellular protein catabolism, resulting in attenuated mTORC1 signaling and compromised anti-viral and anti-tumor T cell responses. The TFE3-protein-mTORC1 signaling axis demonstrates clinical relevance. CD8⁺PD-1⁺ tumor-infiltrating T cells from older patients with lung cancer display reduced lysosomal degradation capacity and impaired cytokine secretion compared to their middle-aged counterparts. This functional defect is rescued by treatment with Vismodegib, a TFE3-inducing drug. Our findings reveal lysosome-mediated extracellular protein catabolism as an important metabolic pathway supporting T cell immunity.

Neoantigens are crucial for antitumor immunity and immune checkpoint inhibitor (ICI) efficacy by triggering strong immune responses. However, conventional methods for identifying neoantigens, such as whole-exon sequencing and short-read RNA sequencing (RNA-seq), appear to be insufficient, and the tumor mutational burden cannot sufficiently predict ICI efficacy. In this study, we employed a proteogenomic approach using long-read RNA-seq with Pacific Biosciences Single-Molecule Real-Time Sequencing technology to analyze full-length transcripts in combination with the human leukocyte antigen ligandome. As a result, many neoantigen candidates were identified, which were unregistered in a comprehensive database, including those from non-coding regions. Additionally, we validated the responses of specific T cell receptors (TCRs) to these candidates and identified several pairs of TCRs and neoantigens. These findings highlight the presence of more diverse neoantigens than expected that cannot be identified by conventional methods.

Metformin shows clinical promise beyond diabetes, yet its immunological safety in non-diabetic contexts remains uncertain. We found that metformin induces apoptosis in double-positive thymocytes across various mouse models and, importantly, creates a "selection trap" by promoting phenotypic maturation (TCRβ⁺CD69⁺) while simultaneously triggering their elimination. Mechanistically, this trap is sprung via mitochondrial dysfunction initiated by complex I inhibition, which causes ATP depletion and elevated mitochondrial reactive oxygen species. This metabolic stress drives sustained AMP-activated protein kinase (AMPK) activation, repurposing extracellular signal-regulated kinase 1/2 signaling to expose the BH3 domain of B cell lymphoma-2 (Bcl-2), thereby neutralizing its anti-apoptotic function. Transcriptomics further reveal that AMPK remodels metabolic pathways to augment oxidative injury and energy crisis, facilitating apoptosis. Notably, thymotoxicity persists even at subtherapeutic doses (25 mg/kg), challenging metformin's indiscriminate use in non-diabetic populations due to risks to central immune homeostasis.

Lupus nephritis (LN) is a leading cause of mortality in systemic lupus erythematosus. While the dominance of Fcγ receptor (FcγR)-activating IgG subclasses has been observed in both human and murine LN, whether this imbalance is causal or merely correlative remains unresolved. To address this, we generated a murine model that exclusively expresses the activating IgG2c while lacking all other IgG subclasses. Despite preserved B cell receptor diversity and intact humoral immunity, these mice developed rapidly progressive and fatal lupus-like nephritis, with 100% mortality by 30 weeks, characterized by extensive renal inflammation. Genetic ablation of FcγRs or complement C3 rescued this phenotype, establishing both as essential and non-redundant mediators of disease. Supporting clinical relevance, renal biopsies from patients with LN exhibited glomerular immune deposits enriched for FcγR-activating IgG1 and minimal inhibitory IgG4. Together, these results identify IgG subclass dominance as a direct driver of LN and provide a fully penetrant, rapid-onset disease model for therapeutic studies.

The FANCD2-FANCI heterodimer contributes to DNA repair at interstrand crosslinks and sites of replication stress. This complex has been physically and mechanistically linked to double-strand break (DSB) repair, but its role in that process remains undefined. Here, we show that the FANCD2-FANCI heterodimer dynamically interacts with open chromatin regions, including transient DSB-induced open chromatin, where it can be stabilized through co-activation by the DNA repair kinase ATM and the Fanconi anemia core ubiquitin ligase. The loaded FANCD2-FANCI heterodimer stabilizes open chromatin and promotes resection and loading of RPA through increased association of BRCA1 and BLM. Chromatin-loaded FANCD2-FANCI has a second, distinct function promoting a G2 cell cycle arrest that is dependent on the ATR-CHK1-WEE1 axis. Our results support a two-step genome surveillance model in which FANCD2-FANCI monitors open chromatin sites and is stably loaded to coordinate DNA repair activities in response to signaling from a DNA repair kinase.