Cell reports最新文献

Here, we report significant changes in the composition of the lung microbiome and metabolome of mice under immune suppression, infection of immunosuppressed mice with virulent and avirulent strains of the clinically important human-pathogenic fungus Aspergillus fumigatus, and treatment with the clinically used antifungal drug voriconazole. Our data also indicate the important role of the gut microbiome for lung homeostasis mediated by the plasma metabolome. In the lung microbiome, DNA sequencing indicates that infection by A. fumigatus leads to a significant increase of anaerobic bacteria, most prominently of Ligilactobacillus murinus; the latter has been confirmed by qPCR analyses. We also isolated live bacteria, including L. murinus, from the murine lower respiratory tract. Co-cultivation of L. murinus and A. fumigatus leads to a reduction in oxygen concentration accompanied by an increase of L. murinus cells, suggesting that A. fumigatus establishes a microaerophilic niche, thereby promoting growth of anaerobic bacteria.

Classical models of efficient coding in neurons assume simple mean responses-"tuning curves"- such as bell-shaped or monotonic functions of a stimulus feature. Real neurons, however, can be more complex: grid cells, for example, exhibit periodic responses that impart the neural population code with high accuracy. But do highly accurate codes require fine-tuning of the response properties? We address this question with the use of a simple model: a population of neurons with random, spatially extended, and irregular tuning curves. Irregularity enhances the local resolution of the code but gives rise to catastrophic, global errors. For optimal smoothness of the tuning curves, when local and global errors balance out, the neural population compresses information about a continuous stimulus into a low-dimensional representation, and the resulting distributed code achieves exponential accuracy. An analysis of recordings from monkey motor cortex points to such "compressed efficient coding." Efficient codes do not require a finely tuned design-they emerge robustly from irregularity or randomness.

The limitations of Hi-C (high-throughput chromosome conformation capture) profiling in in vitro cell culture include failing to recapitulate disease-specific physiological properties and lacking a clinically relevant disease microenvironment. In this study, we conduct Hi-C profiling in a pilot cohort of 12 breast tissues comprising two normal tissues, five ER+ breast primary tumors, and five tamoxifen-treated recurrent tumors. We demonstrate 3D chromatin-regulated breast tumor heterogeneity and identify a looping-mediated target gene, CA2, which might play a role in driving tamoxifen resistance. The inhibition of CA2 impedes tumor growth both in vitro and in vivo and reverses chromatin looping. The disruption of CA2 looping reduces tamoxifen-resistant cancer cell proliferation, decreases CA2 mRNA and protein expression, and weakens the looping interaction. Our study thus provides mechanistic and functional insights into the role of 3D chromatin architecture in regulating breast tumor heterogeneity and informs a new looping-mediated therapeutic avenue for treating breast cancer.

The mosquito Aedes aegypti infects hundreds of millions of people annually with disease-causing viruses. When a mosquito approaches a host, the host often swats defensively. Here, we reveal the mosquito's escape behavior during host seeking in response to a threatening visual cue-a newly appearing shadow. We found that reactions to a shadow are far more aversive when it appears quickly versus slowly. Remarkably, mosquitoes evade shadows under very dim light conditions. Knockout of the TRP channel compromises the ability of mosquitoes to avoid threatening shadows, but only under high light conditions. Conversely, removing two of the five rhodopsins normally present in the compound eyes, Op1 and Op2, diminishes shadow aversion, but only under low light. Upon removal of a threatening visual cue, mosquitoes quickly re-initiate host seeking. Thus, female Aedes balance their need to host seek with visual threat avoidance by rapidly transitioning between these two behavioral states.

REV7, also named MAD2B or MAD2L2, is a subunit of the DNA translesion polymerase zeta and also part of the 53BP1-shieldin complex, which is present at sites of DNA double-strand breaks. REV7 has high sequence similarity to the MAD2 spindle assembly checkpoint protein, prompting us to examine whether REV7 has a checkpoint function. We observed that, in chicken and human cells exposed to agents that induce DNA replication stress, REV7 inhibits mitotic entry; this effect is most evident when the canonical DNA replication stress checkpoint, mediated by ATR, is inhibited. Similar to MAD2, REV7 undergoes conformational changes upon ligand binding, and its checkpoint function depends on its ability to homodimerize and bind its ligands. Notably, even in unchallenged cells, deletion of the REV7 gene leads to premature mitotic entry, raising the possibility that the REV7 checkpoint monitors ongoing DNA replication.

The ubiquitin-26S proteasome system (UPS) is a conserved protein degradation process involved in plant growth and immunity. However, whether some UPS E3 ligases directly target plant viruses in the endoplasmic reticulum (ER) remains less understood. Here, we identify an E3 ubiquitin ligase Hmg-CoA reductase degradation 1 of Nicotiana benthamiana (NbHRD1) interacting with the triple gene block (TGB) movement proteins of beet necrotic yellow vein virus (BNYVV) in the ER. The TGB proteins are ubiquitinated by NbHRD1 and then degraded by the UPS. Consequently, overexpression of NbHRD1a significantly inhibits BNYVV infection, whereas silencing of NbHRD1 promotes BNYVV infection in N. benthamiana. Moreover, NbHRD1a mainly impairs BNYVV cell-to-cell movement, rather than virus replication. Interestingly, NbHRD1 also targets the TGB proteins of potato virus X for ubiquitination and virus inhibition. Collectively, our results demonstrate that NbHRD1 is an important antiviral component targeting plant viruses with TGB movement proteins.

Interferon-gamma (IFN-γ), a cytokine essential for activating cellular immune responses, plays a crucial role in cancer immunosurveillance and the clinical success of immune checkpoint blockade therapy. In this study, we show that Argonaute 2 (AGO2), a key mediator in small RNA-guided gene regulation, inversely correlates with tumor responsiveness to IFN-γ and the efficacy of immunotherapy. Mechanistically, IFN-γ upregulates miR-1246 expression in tumor cells, enhancing its interaction with AGO2. This miR-1246-AGO2 complex disrupts IFN-γ-mediated signal transducer and activator of transcription 1 (STAT1) phosphorylation by stabilizing protein tyrosine phosphatase non-receptor 6 (PTPN6) mRNA, thereby suppressing the expression of downstream C-X-C motif chemokine ligands (CXCLs), IFN-stimulated genes (ISGs), and human leukocyte antigen (HLA) molecules, which collectively contribute to tumor immune evasion. In preclinical cancer models, inhibiting AGO2 with BCI-137 or targeting miR-1246 with its antagomir re-sensitizes tumor cells to IFN-γ, leading to the enhanced recruitment, activation, and cytotoxicity of CD8⁺ T cells and ultimately improving immunotherapy efficacy.

Despite significant progress made in functional genomics, the roles of a relatively small number of essential genes remain enigmatic. Here, we characterize S1 RNA-binding domain-containing protein 1 (SRBD1), an essential gene with no previously assigned function. Through genetic, proteomic, and functional approaches, we discovered that SRBD1 is a DNA-binding protein and a key component of the mitotic chromatid axis. The loss of SRBD1 results in a pronounced defect in sister chromatid segregation that strikingly resembles the phenotype observed when sister chromatid decatenation is perturbed by topoisomerase IIα (TOP2A) dysfunction. Using genetic screens, we uncovered that the requirement for SRBD1 depends on the presence of condensin II but not condensin I. Moreover, we found that SRBD1 activity is most critical during prophase, when chromosome condensation is established. Taking these results together, we propose that SRBD1 acts during prophase to safeguard the decatenation process to prevent the formation of difficult-to-resolve DNA structures, thereby averting severe chromosome missegregations.

Lactate extensively associates with metabolic reprogramming, signal transduction, and immune modulation. Nevertheless, the regulatory role of lactate in immune sensing of cytosolic DNA remains uncertain. Here, we report that lactate serves as an initiator to facilitate proteasomal degradation of cyclic GMP-AMP synthase (cGAS) independent of ubiquitin, thus repressing the production of interferon and contributing to tumor growth. Mechanistically, lactylation of K21 stimulates cGAS translocation from the nucleus to the proteasome for degradation, which is compromised by phosphorylation of PSMA4 S188 via disrupting its association with cGAS. Concurrently, lactylation of K415 rewires PIK3CB activity and impairs ULK1-driven phosphorylation of PSMA4 S188. Physiologically, lactylation of cGAS sustains tumor growth. Expression of cGAS correlates with the antitumor effect of the LDHA inhibitor FX11. Finally, the lactate-cGAS axis indicates a prognostic outcome of lung adenocarcinoma. Collectively, these findings not only put forth a mechanism of cGAS degradation but also unravel the clinical relevance of cGAS lactylation.