Cell reports最新文献

Salivation supports oral health, taste sensation, swallowing, and digestion, but the brain mechanisms that regulate this process remain largely unknown. Here, we identify a salivatory center in the mouse brain stem that integrates sensory and learned anticipatory signals to control salivation. We show that activating choline acetyltransferase-expressing neurons in the inferior salivatory nucleus (IS) is sufficient to trigger saliva secretion. Using fiber photometry, we monitor real-time IS neural responses to mechanosensory and gustatory stimulation and find tight correlation with salivatory output. We further demonstrate that IS neurons receive input from local brain stem circuits, mediating rapid hardwired responses to taste, as well as direct cortical projections. Notably, gustatory cortex input is required for salivatory responses to predictive sensory cues in a Pavlovian conditioning paradigm. Together, our findings define the circuit underlying taste-evoked and anticipatory salivation and provide a foundation for dissecting this autonomic response in health and disease.

Lactate accumulates in large amounts in tumor cells due to the Warburg effect. However, the role of lactate-mediated lactylation, a post-translational modification, in regulating tumor immunity remains unclear. Here, we report that lactate-driven lactylation of STAT1 K193 inhibits interferon (IFN)-γ signaling pathway-mediated tumor immunity. Mechanistically, AARS1 lactylates STAT1 K193 and inhibits its binding to JAK2 and phosphorylation, thereby disrupting tumor responsiveness to IFN-γ, which leads to a reduction in the expression of downstream chemokines, including CXCL9, CXCL10, and CXCL11, ultimately facilitating immune escape of the tumor. Furthermore, we developed a cell-penetrating peptide, K193-pe, that can competitively inhibit STAT1 K193 lactylation and re-sensitize tumor cells to IFN-γ signaling, thus enhancing CD8⁺ T cell recruitment and improving the efficacy of immune checkpoint blockade therapy. Collectively, this study elucidates the functional significance of STAT1 K193 lactylation in tumor immunity and suggests that targeted inhibition of this modification, when paired with immunotherapy, may offer a viable treatment strategy.

Fungal infection induces substantial but poorly understood metabolic reprogramming in macrophages. We demonstrate that fungal stimulation reduces Scap levels in human monocytes and murine bone-marrow-derived macrophages (BMDMs), and Scap deficiency impairs cytokine production and phagocytosis, leading to more severe fungal infections. Although Scap canonically regulates lipid synthesis, pharmacological inhibition of lipid synthesis and genetic ablation of SREBP1/2 reveal that Scap-dependent anti-fungal immunity is largely independent of this pathway. Instead, Scap interacts with and stabilizes PKM2, a key glycolysis enzyme, by competitively inhibiting STUB1-mediated ubiquitination and degradation of PKM2 at Lys-311. PKM2 agonist DASA58 enhances fungus-induced production of pro-inflammatory cytokines and phagocytic activity in wild-type BMDMs and partially rescues these functions in Scap-deficient macrophages, whereas myeloid-specific deletion of PKM2 recapitulates the effects of Scap deficiency. These results identify Scap as a critical regulator of PKM2-mediated glycolysis and demonstrate its potential as a therapeutic target for modulation of anti-fungal immunity.

Patients with triple-negative breast cancer (TNBC) experience high recurrence rates despite current interventions, which include radiation therapy (RT). Tumor cells thought to be involved in recurrence may survive in part due to their interactions with irradiated fibroblasts following treatment. How fibroblasts metabolically respond to RT and influence the behavior of TNBC cells is poorly understood. In this study, we demonstrate that irradiated fibroblasts undergo dynamic mitochondrial changes that are regulated by autophagy, resulting in a metabolic profile characterized by high levels of mitochondrial respiration and fatty acid oxidation. These metabolic adaptations lead to a secretory profile that induces an aggressive phenotype in TNBC cells that is mitigated when fibroblast autophagy is blocked. Our work reveals a burgeoning link between post-RT metabolic adaptations in fibroblasts and crosstalk with TNBC cells that promotes a microenvironment conducive to recurrence.

Many phages encode proteins that specifically inhibit host RNA polymerase activity, thereby sabotaging and, in some cases, hijacking the host transcription machinery to serve their needs. Traditional methods for identifying new phage proteins that inhibit bacterial transcription are labor intensive and require access to live phages. To overcome these limitations, we develop a highly efficient pipeline for AlphaFold 3-guided discovery of phage proteins that inhibit bacterial transcription initiation. Using this pipeline, three phage proteins are identified and characterized. Structural and biochemical analyses demonstrate that these phage proteins bind to distinct sites on RNA polymerase and inhibit transcription initiation via different mechanisms. This study showcases the power of AlphaFold 3 in discovering novel binders of large protein complexes, and the pipeline developed here could be readily adapted to screen modulators of other large targets, such as the ribosome, proteasome, and CRISPR-Cas systems.

Henipaviruses (HNVs) like Nipah virus (NiV) and Hendra virus (HeV) represent severe zoonotic threats. Ghana virus (GhV), identified in 2012, is the only African bat henipavirus with a near-complete genome assembly. However, without isolates in culture, GhV biology, pathogenicity, and zoonotic potential remain poorly understood. Using reverse genetics, we recovered a full-length infectious clone of GhV at BSL-4 following rational reconstruction of its incomplete 3' leader and modification of a non-canonical transcriptional initiation site. GhV demonstrated restricted receptor tropism (ephrin-B2 but not ephrin-B3) and distinct innate immune antagonism. Replication was attenuated in primary human cells but was enhanced in bat cells. In Syrian golden hamsters, GhV infection caused no disease or mortality. Furthermore, a chimeric NiV encoding the GhV receptor-binding protein was completely attenuated in vivo, implicating ephrin-B3 receptor usage as a critical determinant of HNV pathogenesis. These findings elucidate GhV zoonotic potential and inform strategies for virus surveillance and control.

While the cytosolic localization of cGAS is critical for cells to initiate immune responses and protect cells from viral infections, the activity of cGAS in the nucleus is inhibited to prevent autoimmune responses triggered by self-DNA. Therefore, the dynamically regulated distribution of cGAS in the cytosol and nucleus ensures its precise role in maintaining immune homeostasis. However, the molecular mechanism governing this spatial distribution of cGAS remains unclear. Here, we identify MSH6 as a regulator promoting cGAS nuclear localization by enhancing its association with importin-α proteins, consequently reducing cGAS condensation and activity. We further show that MSH6 attenuates antitumor immunity and that its deficiency in tumor cells leads to an effective tumor eradication by heat-inactivated modified vaccinia virus Ankara. Collectively, our results not only provide insights into understanding how cGAS activity is regulated but also suggest a therapeutic potential for treating MSH6-mutated tumors through the cGAS-mediated signaling pathway.

The mechanisms regulating transcriptional changes during brain aging remain poorly understood. Here, we use single-cell epigenomics to profile chromatin accessibility and gene expression across eight mouse brain regions at 2, 9, and 18 months of age. In addition to a marked decline in progenitor populations involved in neurogenesis and myelination, we observe widespread and concordant age-associated changes in transcription and chromatin accessibility across both neuronal and glial cell types. These alterations are accompanied by dysregulation of master transcription factors and a shift toward stress-response programs driven by activator protein 1 (AP-1), indicating progressive drift in cellular identity with aging. We further identify region- and cell-type-specific heterochromatin loss, characterized by increased accessibility at H3K9me3-marked domains, activation of transposable elements, and upregulation of long noncoding RNAs, particularly in glutamatergic neurons. Together, these findings reveal age-related disruption of heterochromatin maintenance and transcriptional regulation, highlighting vulnerable brain regions, cell types, and molecular pathways in brain aging.

Major physiological and developmental innovations are key to land-plant adaptation and evolution, but their genetic basis remains to be fully understood. Here, we show that lipocalins in the moss Physcomitrium patens regulate various physiological and developmental processes. Phylogenetics analyses reveal three major groups of plant lipocalins, including a newly identified group that is restricted to seedless plants. We demonstrate that the temperature-induced lipocalin gene in P. patens (PpTIL) is functionally conserved with flowering plant homologs in response to abiotic stresses. PpTIL not only regulates protonemal development and the transition from two-dimensional to three-dimensional growth but also affects many other processes, such as lipid transport and metabolism, auxin biosynthesis and transport, and chlorophyll catabolism. Further, PpTIL also operates antagonistically with SAFEGUARD1 in protecting chloroplast grana and envelopes from singlet oxygen stress. These findings provide major insights into the role of lipocalins in land-plant evolution.

Macrophage phagocytosis is essential for immune homeostasis but must be tightly constrained to prevent pathological tissue damage. How cellular stress pathways enforce phagocytic homeostasis remains incompletely understood. Here, we show that phagocytosis selectively activates the endoplasmic reticulum stress sensor IRE1α in macrophages, which functions as a negative regulator of lysosome-driven phagocytic amplification. Using myeloid-specific IRE1α-deficient mice and pharmacological inhibition, we demonstrate that loss of IRE1α RNase activity leads to excessive phagocytosis through unchecked lysosomal biogenesis. Mechanistically, phagocytosis-activated IRE1α directly degrades Nr1d1 mRNA via regulated IRE1α-dependent decay (RIDD), thereby restraining NR1D1-driven lysosomal expansion. Disruption of this IRE1α-NR1D1 axis exacerbates macrophage-mediated platelet clearance and accelerates disease progression of immune thrombocytopenia (ITP). Reduced ERN1 expression and IRE1α activity are observed in monocytes from patients with ITP. Pharmacological inhibition of NR1D1 or lysosomal activity rescues thrombocytopenia. Together, these findings establish the IRE1α-NR1D1-lysosome axis as a therapeutically actionable pathway in phagocytosis-driven diseases.