Cell reports最新文献

The acidic environment within the lysosome lumen is essential for its digestive function. However, the source of protons responsible for acidification has remained elusive. Here, using a molecular probe to monitor lysosomal digestion, we discovered enhanced lysosome content degradation at mitochondria-lysosome contact (MLC) sites, which was caused by lysosomal acidification. Using a mitochondrial probe, we observed a proton flux from mitochondria to lysosomes at these MLC sites. Furthermore, we found that physically bringing mitochondria and lysosomes into close proximity can increase lysosome acidification to enhance content digestion under disease conditions. These findings unveil a crucial physiological role of MLCs in cellular functions.

Neutrophils are critical in establishing a tumor-cell-nurturing and immunosuppressive pulmonary "pre-metastatic" niche in breast cancer. The localization and behavior of these neutrophils is, however, not well described. Using multiplexed imaging to investigate the pre-metastatic lung in a spontaneously metastatic mammary cancer model, we uncover that neutrophils with impaired intravascular motility congest the capillaries of pre-metastatic lungs. Slowed neutrophil transit is reversed by activating β₂ integrin with an antibody and can be recapitulated by treating non-tumor-bearing mice with G-CSF. Neutrophil congestion causes a reduction of intravenously injected microbeads in the lung, suggestive of lower perfusion. In a model where tumor cells are injected intravenously into mammary-cancer-bearing Rag1-deficient mice, we observe lower lung experimental metastasis burdens after activating β₂ integrins. Overall, our study proposes that integrin-mediated neutrophil congestion of the alveolar capillaries contributes to the pulmonary pre-metastatic niche.

In a dynamic environment, organisms must continuously update learned action-outcome associations. Central to this flexibility is the prefrontal cortex, whose computations are finely tuned by neuromodulatory inputs. Yet, the temporal dynamics and circuit specificity of this regulation remain unclear. Here, we investigate the contribution of orbitofrontal noradrenaline (OFC-NA) to flexible updating in rats performing an instrumental reversal learning task. Using fiber photometry, we observe transient increases in OFC-NA release following reward deliveries on reversal day, and we find that the magnitude of these responses predicts the speed of behavioral adaptation. Chemogenetic and optogenetic manipulations of NA projections from the locus coeruleus (LC) to the OFC show that perturbing these signals delays reversal learning in a graded, mode-dependent manner, with chemogenetic inhibition having the strongest impact. Together, our findings establish OFC-NA as a temporally precise neuromodulatory mechanism, gating flexible adaptation to changing environmental contingencies.

Systemic chronic inflammation (SCI) is a key driver of non-communicable diseases. Early-life stressors disrupt intestinal homeostasis, promoting SCI, but the mechanisms are unclear. Using translational models, we identify dysregulated iron homeostasis as a pivotal disruptor of intestinal barrier integrity. Single-cell profiling reveals that neutrophils and macrophages mediate iron-dependent mucosal defense. Stress induces iron overload in gut epithelial cells and macrophages, a process governed by the transcription factor MITF. MITF-mediated iron dysregulation in macrophages is associated with neutrophil recruitment to the lamina propria, concomitant with elevated levels of the CXCL8, synchronizing with hepatic inflammatory and metabolic dysregulation via the gut-liver axis. Mechanistically, abnormal iron homeostasis couples with interferon signaling, and MITF modulates iron-related genes (FTH1, TFRC, and FRRS1). Therapeutic mitigation of iron dyshomeostasis preserves barrier function and attenuates systemic inflammation. Our findings identify MITF as a key regulator of gut-liver inflammatory cascades and nominate abnormal iron homeostasis as a target for early-life inflammatory disorders.

Cancer is an evolutionary process characterized by profound intratumor heterogeneity (ITH), which can be quantified using in silico estimates of cancer cell fractions (CCFs) of tumor-specific somatic mutations. We demonstrate a data-driven approach based on CCF distributions to identify 4 robust pan-cancer evolutionary signatures from 4,146 tumors across 17 cancer types in The Cancer Genome Atlas (TCGA). These signatures define a continuum of cancer cell fractions reflecting neutral evolution, clonal expansion, and clonal fixation. Correlating evolutionary signatures with mutational and biological programs reveals that tumors enriched for clonal expansion and fixation are associated with immune evasion and distinct changes in the tumor immune microenvironment. Our analysis reveals a dynamic shift from adaptive to innate immune programs as tumors progress toward clonal fixation and escape immune surveillance, accompanied by the clonal expansion of driver genes modulating tumor-stroma interactions. These evolutionary dynamic subtypes are further associated with clinical outcomes and immunotherapy responses.

T cell receptor (TCR) signaling plays a crucial role in T cell activation by creating a negative controlling mechanism to limit the strength of immune activation; however, the underlying mechanisms remain to be fully elucidated. Here, we identify the small ubiquitin-like modifier (SUMO)-specific protease 1 (SENP1) as a target of the TCR-NF-κB signaling pathway that negatively regulates TCR-induced CD8⁺ T cell activation. SENP1 deficiency promotes the early occurrence of TCR-induced CD8⁺ T cell proliferation and effector gene expression. Mechanistically, the nuclear receptor NR4A1 is identified as a deSUMOylation target of SENP1 during this process. SENP1-mediated deSUMOylation of NR4A1 enhances its suppressive effect on the expression of TCR-induced effector genes in CD8⁺ T cells. Deficiency in the SENP1-NR4A1 axis markedly enhances the CD8⁺ T cell response against L. monocytogenes infection. Collectively, these findings identify SENP1 as a crucial regulator that integrates TCR-NF-κB signaling with NR4A1 activity to fine-tune the CD8⁺ T cell-mediated immune response.

How cancer cells exploit the tumor microenvironment (TME) to alleviate oxidative stress remains largely unclear. Here, we show that nociceptive neurons, via secretion of epiregulin, increase Lnc-GCLC-1 expression in cancer cells, thereby protecting them against oxidative stress-induced cell death in head and neck squamous cell carcinoma (HNSCC). Specifically, nociceptive neurons increase Ets variant 4 (ETV4)-mediated Lnc-GCLC-1 expression in cancer cells upon oxidative stress. Increased cellular Lnc-GCLC-1 interacts with and ubiquitinates Kelch-like ECH-associated protein 1 (KEAP1), leading to disruption of the KEAP1-NRF2 interaction and subsequent activation of the NRF2 signaling pathway. This enhances GSH biosynthesis in cancer cells and protects them against cisplatin-induced oxidative stress. Targeting nociceptive neurons or the EREG-Lnc-GCLC-1-NRF2 axis therefore improves the therapeutic efficacy of cisplatin. Moreover, high Lnc-GCLC-1 levels correlate with poor prognosis in patients with HNSCC. Our study sheds light on nociceptive neurons as accomplices that assist HNSCC cells in surviving oxidative stress.

The molecular details of macrophage-fibroblast crosstalk during the onset and resolution of inflammatory disease remain incompletely understood. Here, we apply a bioinformatic modeling approach based on single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing to map heterocellular signaling circuits of synovial macrophage and synovial fibroblast (SF) subsets during various stages of inflammatory arthritis. While SFs function as key pacemakers of synovial inflammation, individual subsets of synovial macrophages support both the perpetuation and the resolution of arthritis. Pro-inflammatory Il1b⁺ macrophages dominate the early stages of inflammation and retain a substantial intrinsic plasticity that is characterized by chromatin remodeling and an eventual differentiation into Spp1⁺ macrophages. These cells display a terminally differentiated phenotype, suppress the activation of pro-inflammatory SFs, and initiate the resolution of arthritis by secretion of regulatory mediators, including osteopontin. Our data highlight the dichotomous character of macrophage-fibroblast crosstalk and define the cellular and molecular checkpoints that control the onset and resolution of immune-mediated inflammatory diseases.

Flower aging, or senescence, is generally accompanied by petal dehydration/wilting. The cuticle functions as a barrier to withhold water for plant organs. However, little is known about how the cuticle modifies the process of petal development. Here, we report that cuticular wax is dynamically changed during petal senescence and wax coverage on petals is coordinated with the expression of TgWIN1. Functional identification indicates that TgWIN1 positively regulates wax accumulation and delays petal senescence. TgNAC2 promotes petal senescence by inhibiting TgWIN1 expression in senescent petals, while TgFbox1 degrades TgNAC2 protein accumulation via ubiquitination. Additionally, both abscisic acid (ABA) and ethylene contribute to petal senescence by promoting TgNAC2 expression but inhibiting TgFbox1 expression, respectively. Thus, we propose an ABA/ethylene-mediated TgFbox1-TgNAC2-TgWIN1 module that precisely regulates the cuticular wax biosynthesis and petal senescence, offering potential targets for optimizing flower longevity and wax biosynthesis in plants.

Aging is an unavoidable part of life, but gaps still remain in the understanding of age-associated molecular changes within the brain. We generated single-nucleus multiome ATAC plus gene expression profiles in 357 human brain samples from European and African admixed ancestry individuals ranging from 15 to 100 years old. The final dataset consisted of paired transcriptomic and epigenomic profiles for over 1.5 million cells. These were classified into seven major cell types using canonical marker genes, and each type was analyzed for features associated with aging. Open chromatin regions were correlated with transcription factor expression to identify age-associated regulatory networks, and co-accessibility identified linked peaks and genes, revealing a catalog of putative cis-regulatory elements by cell type. These multiomic data serve as a resource to characterize transcriptional regulation by cell type and generate hypotheses about how these distinct profiles both influence and are influenced by aging and disease.