Cell reports最新文献

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.

Intrinsically disordered regions (IDRs) are essential regulators of protein function despite lacking stable secondary and tertiary structures. IDRs are integral to the function of multidomain regulatory proteins, such as the essential transcriptional coactivators cAMP response element-binding protein (CREB)-binding protein (CBP) and EP300 (p300), but how their multiple IDRs work together to regulate function remains poorly understood. Here, we demonstrate that different CBP-IDRs cooperate to control complex nuclear behaviors. We show how CBP-IDRs with different sequence properties make unique contributions to CBP behavior, establishing a critical balance between positive and negative regulation of CBP condensates. These opposing interactions are functionally important, tuning CBP's sensitivity to regulatory cues such as lysine acetylation. Disruption of this balance fundamentally alters CBP's chromatin occupancy, patterns of histone acetylation, and downstream gene expression. Together, our work reveals an unexpected mechanism of intramolecular cooperation between distinct IDRs and highlights how their properties shape the functional landscape of multi-domain proteins.

Immunotherapy has transformed the treatment of non-small cell lung cancer (NSCLC). Yet, acquired resistance remains a major clinical challenge. Defining molecular determinants of tumor sensitivity to T cell-mediated killing is therefore critical. Tumor necrosis factor α (TNF-α) released by cytotoxic T cells promotes tumor cell death, whereas NF-κB signaling supports survival. Autophagy counteracts TNFα-induced apoptosis, and its inhibition enhances responses to immune checkpoint inhibitors (ICIs). Genomic alterations further contribute to immune evasion and reduced immunotherapy efficacy. We previously identified DSTYK, a dual serine/threonine and tyrosine kinase amplified in NSCLC, as a suppressor of TNF-α-mediated CD8⁺ T cell killing and a driver of ICI resistance through autophagy. Here, we show that DSTYK modulates TNFR1 signaling by phosphorylating the autophagy initiator ULK1, which enables ULK1-dependent phosphorylation of RIPK1. Loss of DSTYK disrupts ULK1 activation, promotes RIPK1 autophosphorylation, proapoptotic signaling, and impaired NF-κB-dependent survival. These findings define a DSTYK-ULK1-RIPK1 axis controlling TNF-α-induced apoptosis and support targeting ULK1 to sensitize DSTYK-amplified NSCLC to T cell-mediated killing.

Herpes simplex encephalitis (HSE) is a life-threatening disease of the central nervous system caused by herpes simplex virus type 1 (HSV-1). Despite being a standard treatment, antiviral acyclovir and its derivatives often face limitations in clinical application due to their side effects and viral drug resistance. Inspired by viral entry through recognition of nectin-1 on the host cell surface, we engineered enucleated mesenchymal stem cells with high nectin-1 expression (eMSCs) to serve as "decoys" for capturing HSV-1. We found that eMSCs competitively captured the virus in the presence of neurons while inhibiting its replication and spread by removing the nucleus in advance. Interestingly, due to the absence of nuclei, eMSCs capturing the virus trigger macrophage efferocytosis through intrinsic apoptosis after approximately 60 h, thereby accelerating existing viral clearance. This is a property lacking in current antiviral drugs, including ACV. In summary, this strategy significantly improved the quality of life of HSE mice.