Cell reports最新文献

Peripheral nerves regenerate following injury, in contrast to those of the central nervous system. This involves the collective migration of Schwann cell (SC) cords, which transport regrowing axons across the wound site. The SC cords migrate along a newly formed vasculature, which bridges the wound site in response to vascular endothelial growth factor, secreted by hypoxic macrophages. However, the directional signals by which SC cords navigate the long distances across the wound, in the absence of those that guide axons during development, remain unknown. Here, we identify CCL3 as the SC chemotactic factor, secreted by hypoxic macrophages, responsible for this process. We show that CCL3 promotes collective SC migration and axonal regrowth in vivo and, using genetic mouse models and widely used CCL3 inhibitors, that CCL3 is essential for effective nerve regeneration. These findings have therapeutic implications for both promoting nerve repair and inhibiting the aberrant nerve growth associated with trauma and disease.

Repeated vaccinations and infections have led to diverse states of hybrid immunity against SARS-CoV-2 in the global population. However, age and comorbidities can compromise protection against severe disease, and antibody-mediated immunity is undercut by viral immune escape mutations. Whether and to what extent durable T cell responses compensate for reduced humoral immunity, particularly in the elderly, have not been investigated. Here, we utilize SARS-CoV-2-specific and pan-coronavirus-derived peptide pools, including or excluding spike glycoprotein-derived epitopes, to measure vaccination and infection induced pan-human endemic coronavirus (PHEC)-directed T cell immunity. In contrast to vaccinated individuals, hybrid immunity induced by vaccination and SARS-CoV-2 infection comprises high frequencies of PHEC-reactive T cells with comparable frequencies and functional TCR avidities across all age groups. With waning humoral immunity and vulnerability to escape mutations, PHEC-reactive T cells may provide critical protection. Our findings underscore the importance of incorporating pan-coronavirus T cell epitopes in future vaccine strategies.

The germinal center (GC) sets an environment where antigen-specific B cells are compelled to continuously increase their affinity to compete for the antigen and obtain Tfh help for survival and propagation. Previous studies indicated that low-affinity B cells are disadvantaged in the presence of high-affinity ones, suggesting that competition may lead to the elimination of low-affinity B cells and their descendants. However, using a multivalent virus-mimicking antigen, our study demonstrates that low-affinity B cells not only successfully participate in GC responses alongside high-affinity B cells but also undergo accelerated affinity maturation under the more stringent competition. Furthermore, our cryo-electron-microscopy-based structural analysis reveals that both low-affinity and high-affinity B cells compete for the same antigenic epitope. Although the applicability of this idealized GC competition to true pathogen-induced responses remains uncertain, this change in perspective on the role of competition in low-affinity B cell evolution provides valuable insights for vaccine development.

Dendritic cells (DCs) present exogenous antigens via major histocompatibility complex class I (MHC-I) and MHC class II (MHC-II) molecules, activating CD8⁺ and CD4⁺ T cells. A critical but poorly understood step in this process is the trafficking of peptide-loaded MHC molecules from the endocytic system to the cell surface. In this study, we demonstrate that the Golgi reassembly-stacking protein of 55 kDa (GRASP55), which has been shown to have no role in stacking, is essential for antigen presentation. Using soluble, bead-coated, and bacterial-bound antigens, we found significantly impaired exogenous antigen presentation in GRASP55-deficient bone-marrow-derived DCs (BMDCs). Notably, GRASP55 was recruited to late phagosomes, and our data suggest that it is crucial for sorting MHC-I and MHC-II molecules, facilitating their trafficking to the plasma membrane. Our findings highlight the vital role of GRASP55 in the intracellular transport of MHC molecules bound to their respective peptides during exogenous antigen presentation.

Microtubules are polymers required for chromosome segregation. Their drug-induced hyperstabilization impairs chromosome segregation and is an established anti-cancer therapy. How cells respond to microtubule hyperstabilization, however, is incompletely understood. To study this, we evolved budding yeast cells expressing a microtubule-hyperstabilizing tubulin mutant and isolated adapted strains. Aneuploidy of specific chromosomes carrying the microtubule regulators STU2 and VIK1/KAR3 was the first observable adaptation. In the longer run, aneuploidies were outcompeted by mutations in α- or β-tubulin, partially overlapping with mutations in cancer patients. Thus, compensation of microtubule hyperstabilization follows a restrained and reproducible path where new mutations combine with the original offending mutation on the same carrier. While partly compensatory, several mutations failed to re-establish fully normal microtubule dynamics. Sustained growth relied on the mitotic checkpoint, indicating that extended mitotic timing limits the genomic instability caused by reduced microtubule dynamics. Our results predict a potential vulnerability of cells resistant to microtubule-hyperstabilizing agents.

Amplification of the androgen receptor (AR) locus is the most frequent alteration in metastatic castration-resistant prostate cancer (CRPC). Recently, it was discovered that an enhancer of the AR is co-amplified with the AR gene body and contributes to increased AR transcription and resistance to androgen deprivation therapy. However, the mechanism of enhancer activation in advanced disease is unknown. Here, we used CRISPR-Cas9 screening to identify transcription factors that bind to the AR enhancer and modulate enhancer-mediated AR transcription. We demonstrate that HOXB13, GATA2, and TFAP2C bind the AR enhancer in patient-derived xenografts and directly impact features associated with an active chromatin state. Interestingly, the AR enhancer belongs to a set of regulatory elements that require HOXB13 to maintain FOXA1 binding, further delineating the role of HOXB13 in CRPC. This work provides a framework to functionally identify trans-acting factors required for the activation of disease-related noncoding regulatory elements.

Macroautophagy/autophagy is crucial for cell survival during nutrient starvation. Autophagy requires the coordinated function of several Atg proteins, including the Atg1 kinase, for efficient induction and execution. Recently, several RNA-binding proteins (RBPs) have been shown to post-transcriptionally regulate ATG1. However, a comprehensive understanding of autophagy regulation by RBPs via ATG1 is yet to be elucidated. Here, we utilize an in vitro approach to identify RBPs that specifically interact with ATG1 untranslated regions. We show that Npl3 and Pub1 interact with the ATG1 5' and 3' untranslated regions during nitrogen starvation. Furthermore, Npl3 and Pub1 coordinate to facilitate ATG1 mRNA export to the cytoplasm and its subsequent interaction with the translational machinery. Significantly, in non-small cell lung cancer cell lines, mammalian Pub1, TIA1, also positively regulates ULK1 protein expression and autophagy during serum starvation. Overall, our study highlights the regulatory landscape that fine-tunes Atg1 protein expression to sustain autophagy during nutrient starvation.

Epigenome, transcriptome, and proteome analyses of postmortem brains have revealed initial molecular insights into cocaine use disorder (CUD). However, the inter-relationship between these omics and the contribution of individual cell types remains largely unknown. We present an in-depth analysis of molecular changes in the ventral striatum in CUD at multi-omics and single-cell resolution. Integrative multi-omics analyses of microRNA sequencing (microRNA-seq), RNA sequencing (RNA-seq), and proteomics datasets in 41 individuals and single-nuclei RNA-seq in a subset of 16 individuals revealed conserved deregulation of metabolic pathways, oxidative phosphorylation, and glutamatergic signaling. Cell type-specific analyses identified inverse metabolic pathway deregulation patterns in glial and neuronal cells, notably in astrocytes and medium-spiny neurons (MSNs). Characterizing astrocyte-neuron crosstalk revealed altered glutamatergic and cell-cell adhesion signaling in CUD. By applying a comprehensive multi-omics analytical framework, our study provides novel insights into CUD-associated molecular changes in the ventral striatum highlighting the perturbation of astrocytes, MSNs, and their crosstalk in CUD.

Intratumoral heterogeneity drives cancer progression and influences treatment outcomes. The mechanisms underlying how cellular subpopulations communicate and cooperate to impact progression remain largely unknown. Here, we use collective invasion as a model to deconstruct processes underlying non-small cell lung cancer subpopulation cooperation. We reveal that collectively invading packs consist of heterogeneously cycling and non-cycling subpopulations using distinct pathways. We demonstrate that the follower subpopulation secretes transforming growth factor beta one (TGF-β1) to stimulate divergent subpopulation responses-including proliferation, pack cohesion, and JAG1-dependent invasion-depending on cellular context. While isolated followers maintain proliferation in response to TGF-β1, isolated leaders enter a quiescence-like cellular state. In contrast, leaders within a heterogeneous population sustain proliferation to maintain subpopulation proportions. In vivo, both leader and follower subpopulations are necessary for macro-metastatic disease progression. Taken together, these findings highlight that intercellular communication preserves tumor cell heterogeneity and promotes collective behaviors such as invasion and tumor progression.