Cell reports最新文献

Interactions between metastatic cancer cells and the brain microenvironment regulate brain metastasis (BrMet) progression. Central nervous system (CNS)-native and peripheral immune cells influence the BrMet immune landscape, but the dynamics and factors modulating this microenvironment remain unclear. As the gut microbiome impacts CNS and peripheral immune activity, we investigated its role in regulating immune response dynamics throughout BrMet stages. Antibiotic-induced (ABX) gut dysbiosis significantly increased BrMet burden versus controls but was equalized with fecal matter transplantation, highlighting microbiome diversity as a regulator of BrMet. Single-cell sequencing revealed a highly dynamic immune landscape during BrMet progression in both conditions. However, the timing of the monocyte inflammatory response was altered. Microglia displayed an elevated activation signature in late-stage metastasis in ABX-treated mice. T cell and microglia perturbation revealed involvement of these cell types in modulating BrMet under gut dysbiosis. These data indicate profound effects on immune response dynamics imposed by gut dysbiosis across BrMet progression.

Arginine plays a critical role in colorectal cancer (CRC) progression. We find that arginine catabolism is reduced in the intestinal microbiota of patients with CRC but increased in tumor tissue. We further verify that Escherichia coli can consume arginine via the arginine succinyltransferase (AST) pathway, and gavaging mice with the AST-deficient E. coli Nissle 1917 (ΔacEcN) can inhibit arginine catabolism of the intestinal microbiota, thereby increasing the arginine concentration in the colon. In the azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC mouse model, reduced arginine catabolism in the intestinal microbiota increases the arginine concentration in the tumor microenvironment, thereby activating the nitric oxide (NO) synthesis pathway and polyamine synthesis pathway in tumor tissues, stimulating angiogenesis in the tumor microenvironment, inducing M2 macrophage polarization, and activating the Wingless/Integrated (Wnt)/β-catenin pathway, ultimately accelerating CRC progression. This study reveals that intestinal microbiota can affect CRC progression through arginine catabolism, providing a potential target for the prevention and therapy of CRC.

The catalytic role of U6 snRNP in pre-mRNA splicing has been well established. In this study, we utilize an antisense morpholino oligonucleotide (AMO) specifically targeting catalytic sites of U6 snRNA to achieve functional knockdown of U6 snRNP in HeLa cells. The data show a significant increase in global intronic premature cleavage and polyadenylation (PCPA) events, similar to those observed with U1 AMO treatment, as demonstrated by mRNA 3'-seq analysis. Mechanistically, we provide evidence that U6 AMO-mediated splicing inhibition might be the driving force for PCPA as application of another specific AMO targeting U2 snRNP results in similar global PCPA effects. Together with our recently published findings that demonstrate the global inhibitory effect of U4 snRNP on intronic PCPA, our data highlight the critical role of splicing in suppressing intronic PCPA and support a model in which splicing and polyadenylation may compete with each other within introns during co-transcriptional mRNA processing.

Neurogenesis and gliogenesis continue in the ventricular-subventricular zone (V-SVZ) of the adult rodent brain. V-SVZ astroglial cells with apical contact with the ventricle (B1 cells) function as neural stem cells (NSCs). B1 cells sharply decline during early postnatal life; in contrast, neurogenesis decreases at a slower rate. Here, we show that a second population of astroglia (B2 cells) that do not contact the ventricle also function as NSCs in the adult mouse brain. B2 cell numbers increase postnatally, are sustained in adults, and decrease with aging. We reveal the transcriptomic profile of B1 and B2 cells and show that, like B1 cells, B2 cells can be quiescent or activated. Transplantation and lineage tracing of B2 cells demonstrate their function as primary progenitors for adult neurogenesis. This study reveals that NSC function is progressively relayed from B1 to B2 progenitors helping explain how neurogenesis is maintained into adult life.

Transient memories are converted to persistent memories at the synapse and circuit/systems levels. The synapse-level consolidation parallels electrophysiological transition from early- to late-phase long-term potentiation of synaptic transmission (E-/L-LTP). While glutamate signaling upregulations coupled with dendritic spine enlargement are common underpinnings of E-LTP and L-LTP, synaptic mechanisms conferring persistence on L-LTP remain unclear. Here, we show that L-LTP induced at the perforant path-hippocampal dentate gyrus (DG) synapses accompanies cytoskeletal remodeling that involves actin and the septin subunit SEPT3. L-LTP in DG neurons causes fast spine enlargement, followed by SEPT3-dependent smooth endoplasmic reticulum (sER) extension into enlarged spines. Spines containing sER show greater Ca²⁺ responses upon synaptic input and local synaptic activity. Consistently, Sept3 knockout in mice (Sept3^-/-) impairs memory consolidation and causes a scarcity of sER-containing spines. These findings indicate a concept that sER extension into active spines serves as a synaptic basis of memory consolidation.

Mitochondrial antiviral signaling protein (MAVS) is a central adaptor protein in retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling against RNA viral infection. Posttranslational modifications (PTMs) play a critical role in modulating the activity of MAVS. However, how phase separation regulates the PTMs to fine-tune MAVS activation remains to be elucidated. In this study, we identify Toll-interacting protein (TOLLIP) as a negative regulator of RLR signaling. A deficiency of TOLLIP leads to an enhanced type I interferon response upon RNA viral infection. Mice with the deletion of TOLLIP are more resistant to lethal vesicular stomatitis virus (VSV) infection than wild-type counterparts. Mechanistically, TOLLIP forms condensates that rely on its intrinsically disordered region (IDR). TOLLIP condensates interact with SENP1, promote the aggregation of SENP1, and enhance the interaction between SENP1 and MAVS, consequently leading to deSUMOylation and less aggregation of MAVS. Overall, our study reveals the critical role of TOLLIP condensation in regulating the activation of MAVS, emphasizing the complexity of MAVS activity modulation.

The small ubiquitin-related modifier SUMO regulates cellular processes in eukaryotes either by modulating individual protein-protein interactions or with relaxed substrate selectivity by group modification. Here, we report the isolation and characterization of designed ankyrin repeat protein (DARPin)-based affinity probes directed against budding yeast SUMO (Smt3). We validate selected DARPins as compartment-specific inhibitors or neutral detection agents. Structural characterization reveals a recognition mode distinct from that of natural SUMO interactors. In vivo application pinpoints Smt3's essential function to the nucleus and demonstrates DARPin-mediated sensitization toward various stress conditions. A subset of selected clones is validated as SUMOylation reporters in cells. In this manner, we identify a DNA-damage-induced nuclear SUMOylation response that-in contrast to previously reported chromatin group SUMOylation-is independent of single-stranded DNA and the SUMO-E3 Siz2 but depends on Mms21 and likely reflects late intermediates of homologous recombination. Thus, Smt3-specific DARPins can provide insight into the dynamics of SUMOylation in defined subcellular structures.

Despite advances in cancer treatment, the development of effective therapies remains an urgent unmet need. Here, we investigate the potential of bacteria-derived metabolites as a therapeutic alternative for the treatment of cancer. We detect 3-hydroxydodecanedioic acid in the serum of tumor-bearing mice treated with serum from mice previously supplemented with a mix of Clostridiales bacteria. Further, 3-hydroxydodecanoic acid, an intermediate derivative between dodecanoic and 3-hydroxydodecanedioic acids, exhibits a strong anti-tumor response via GPR84 receptor signaling and enhances CD8⁺ T cell infiltration and cytotoxicity within tumor tissue in multiple cancer models. Metabolomics analysis of colorectal cancer patient serum reveals an inverse correlation between the abundance of these metabolites and advanced disease stages. Our findings provide a strong rationale for 3-hydroxydodecanoic acid and the GPR84 receptor to be considered as promising therapeutic targets for cancer treatment.

X chromosome inactivation (XCI) equalizes X-linked gene expression between sexes. B cells exhibit dynamic XCI, with Xist RNA/heterochromatic marks absent on the inactive X (Xi) in naive B cells but returning following mitogenic stimulation. The impact of dynamic XCI on Xi structure and maintenance was previously unknown. Here, we find dosage compensation of the Xi with state-specific XCI escape genes in naive and in vitro-activated B cells. Allele-specific OligoPaints indicate similar Xi and active X (Xa) territories in B cells that are less compact than in fibroblasts. Allele-specific Hi-C reveals a lack of TAD-like structures on the Xi of naive B cells and stimulation-induced alterations in TAD-like boundary strength independent of gene expression. Notably, Xist deletion in B cells changes TAD boundaries and large-scale Xi compaction. Altogether, our results uncover B cell-specific Xi plasticity, which could underlie sex-biased biological mechanisms.

The bypass of DNA lesions by translesion synthesis (TLS) polymerases is a critical step for DNA damage tolerance, allowing the completion of DNA synthesis. It has been under debate whether TLS-mediated bypass restarts stalled forks or occurs post-replicationally. We developed cell imaging techniques based on proximity ligation to monitor the recruitment of TLS polymerases Polκ and Polη to DNA adducts. We show that this recruitment is adduct specific, with Polκ being preferentially recruited to benzo[a]pyrene diol epoxide (BPDE) lesions and Polη to cisplatin lesions. The recruitment depends on the primase-polymerase PrimPol, which reprimes downstream of stalled forks to restart DNA synthesis. TLS polymerase deficiency results in the accumulation of single-stranded DNA (ssDNA) gaps in an adduct-specific manner, which are processed into double-strand breaks (DSBs). Our findings argue that TLS occurs mainly behind the restarted replication fork in order to fill PrimPol-derived gaps and is essential to suppress the nucleolytic conversion of ssDNA gaps into cytotoxic DSBs in a lesion-specific manner.