Cell reports最新文献

Metabolic enzymes play a central role in cancer metabolic reprogramming, and their dysregulation creates vulnerabilities that can be exploited for therapy. However, accurately measuring metabolic enzyme activity in a high-throughput manner remains challenging due to the complex, multi-layered regulatory mechanisms involved. Here, we present iMetAct, a framework that integrates metabolic-transcription networks with an information propagation strategy to infer enzyme activity from gene expression data. iMetAct outperforms expression-based methods in predicting metabolite conversion rates by accounting for the effects of post-translational modifications. With iMetAct, we identify clinically significant subtypes of hepatocellular carcinoma with distinct metabolic preferences driven by dysregulated enzymes and metabolic regulators acting at both the transcriptional and non-transcriptional levels. Moreover, applying iMetAct to single-cell RNA sequencing data allows for the exploration of cancer cell metabolism and its interplay with immune regulation in the tumor microenvironment. An accompanying online platform further facilitates tumor metabolic analysis, patient stratification, and immune microenvironment characterization.

Chronic inflammation and a decline in mitochondrial function are hallmarks of aging. Here, we show that the two mechanisms may be linked. We found that interleukin-6 (IL6) suppresses mitochondrial function in settings where PGC1 (both PGC1α and PGC1β) expression is low. This suppression is mediated by the JAK1/STAT1/3 axis, which activates HIF1α through non-canonical mechanisms involving upregulation of HIF1A and ERRα transcription, and subsequent stabilization of the HIF1A protein by ERRα. HIF1α, in turn, inhibits ERRα, which is a master regulator of mitochondrial biogenesis, thus contributing to the inhibition of mitochondrial function. When expressed at higher levels, PGC1 rescues ERRα to boost baseline mitochondrial respiration, including under IL6-treated conditions. Our study suggests that inhibition of the IL6 signaling axis could be a potential treatment for those inflammatory settings where mitochondrial function is compromised.

Face processing models propose gradually more complex receptive field properties culminating in invariant representations in anterior inferotemporal cortex (aITC), leading to late socio-emotionally relevant encoding in pre- and orbitofrontal cortex (POC). Top-down facilitation models, however, predict that some lower-level POC neurons respond faster than aITC. To resolve this discrepancy, we recorded from 2,459 neurons in fMRI-defined POC and aITC face patches. POC patches are more heterogeneous, containing smaller fractions of face-selective neurons than aITC and a mixture of responses to faces and non-faces. In one POC patch, face responses are surprisingly fast, outpacing those in aITC. Moreover, its responses correlate inversely with stimulus spatial frequency. Hence, our extensive data, with a large diversity of POC neurons, support both models and suggest one POC face patch might be specialized in fast, low-level face processing, which may enable (partially) invariant face representations during subsequent processing stages in inferotemporal cortex (ITC).

During peripheral nervous system development, Schwann cells undergo Rac1-dependent cytoskeletal reorganization as they insert cytoplasmic extensions into axon bundles to sort and myelinate individual axons. However, our understanding of the direct effectors targeted by Rac1 is limited. Here, we demonstrate that striatin-3 and MOB4 are Rac1 interactors. We show that Schwann-cell-specific ablation of striatin-3 causes defects in lamellipodia formation, and conditional Schwann cell knockout for striatins presents a severe delay in radial sorting. Finally, we demonstrate that deletion of Rac1 or striatin-1/3 in Schwann cells causes defects in the activation of Hippo pathway effectors YAP and TAZ and the expression of genes co-regulated by YAP and TAZ, such as extracellular matrix receptors. In summary, our results indicate that striatin-3 is a Rac1 interactor and that striatins are required for peripheral nervous system development and reveal a role for Rac1 in the regulation of the Hippo pathway in Schwann cells.

The migration of newborn neurons is essential for brain morphogenesis and circuit formation, yet controversy exists regarding how neurons generate the driving force against strong mechanical stresses in crowded neural tissues. We found that cerebellar granule neurons employ a mechanosensing mechanism to switch the driving forces to maneuver in irregular brain tissue. In two-dimensional (2D) cultures, actomyosin is enriched in the leading process, exerting traction force on the cell soma. In tissue or 3D confinement, however, actomyosin concentrates at the posterior cell membrane, generating contractile forces that assist passage through narrow spaces, working alongside the traction force in the leading process. The 3D migration is initiated by the activation of a mechanosensitive channel, PIEZO1. PIEZO1-induced calcium influx in the soma triggers the PKC-ezrin cascade, which recruits actomyosin and transmits its contractile force to the posterior plasma membrane. Thus, migrating neurons adapt their motility modes in distinct extracellular environments in the developing brain.

The absence of HIBCH or ECHS1, two Leigh syndrome genes, in cultured cells results in abnormal mitochondrial morphology and respiratory defects. Fly eyes lacking either protein exhibit age-dependent degeneration. Elevated lysine methacrylation (Kmea) is observed in both HIBCH- and ECHS1-deficient cells and fly tissues. Quantitative mass spectrometry reveals that many proteins are ectopically modified by Kmea in these cells. Mimicking Kmea in proteins like CH60, FKBP4, BIP, LDHB, or DHRS2 replicates the mitochondrial morphology changes seen in HIBCH- or ECHS1-deficient cells. Reducing Kmea modification partially rescues mitochondrial morphology changes in cells and eye degeneration in flies. Fibroblasts from patients with HIBCH or ECHS1 mutations show similar mitochondrial changes and elevated Kmea, which are significantly reversed by administering N-acetyl-L-cysteine to reduce Kmea levels. We propose that ectopic Kmea modification mediates the defects caused by HIBCH- or ECHS1-deficiency. Reducing Kmea modification provides a new approach for treating HIBCH- or ECHS1-related Leigh syndrome.

The Duox-reactive oxygen species (ROS) system and the immune deficiency (Imd) pathway play a major role in insect gut immunity. However, their interaction to accomplish an effective immune response is still unclear. Here, we show that Duox regulates the peritrophic matrix (PM) and further affects the Imd immune response to pathogens in Bactrocera dorsalis. This regulation requires a nuanced ROS balance: low H₂O₂ increases PM permeability, while higher H₂O₂ damages the PM during infection. Importantly, we found that gut commensal bacteria ensured proper Duox-dependent ROS production and PM stability, thus preventing Imd pathway overactivation in response to pathogens. We conclude that gut commensal bacteria-induced Duox-ROS is crucial for maintaining PM structural homeostasis, and the PM, in turn, regulates Imd pathway activation and protects intestinal epithelial cells. Thus, our study reveals a crosstalk between the PM barrier and Imd-mediated antibacterial function to ensure host defense in the gut.

Gamma-frequency oscillations are a hallmark of active information processing and are generated by interactions between excitatory and inhibitory neurons. To examine the contribution of distinct inhibitory interneurons to visually induced gamma oscillations, we recorded from optogenetically identified PV+ (parvalbumin) and Sst+ (somatostatin) interneurons in mouse primary visual cortex (V1). PV and Sst inhibitory interneurons exhibited distinct correlations to gamma oscillations. PV cells were strongly phase locked, while Sst cells were weakly phase locked, except for narrow-waveform Sst cells. PV cells fired at a substantially earlier phase in the gamma cycle (≈6 ms) than Sst cells. PV cells fired shortly after the onset of tightly synchronized burst events in excitatory cells, while Sst interneurons fired after subsequent burst spikes or single spikes. These findings indicate a main role of PV interneurons in synchronizing network activity and suggest that PV and Sst interneurons control the excitability of somatic and dendritic neural compartments with precise time delays coordinated by gamma oscillations.

Forkhead box protein P1 (FOXP1), a transcription factor enriched in the neocortex, is associated with autism spectrum disorders (ASDs) and FOXP1 syndrome. Emx1^Cre/+;Foxp1^fl/fl conditional deletion (Foxp1 conditional knockout [cKO]) in the mouse cortex leads to overall reduced cortex thickness, alterations in cortical lamination, and changes in the relative thickness of cortical layers. However, the developmental and cell-type-specific mechanisms underlying these changes remained unclear. We find that Foxp1 deletion results in accelerated pseudo-age during early neurogenesis, increased cell cycle exit during late neurogenesis, altered gene expression and chromatin accessibility, and selective migration deficits in a subset of upper-layer neurons. These data explain the postnatal differences observed in cortical layers and relative cortical thickness. We also highlight genes regulated by FOXP1 and their enrichment with high-confidence ASD or synaptic genes. Together, these results underscore a network of neurodevelopmental-disorder-related genes that may serve as potential modulatory targets for postnatal modification relevant to ASDs and FOXP1 syndrome.

Polycomb repressive complexes PRC1 and PRC2 control lineage-specific gene silencing during early embryogenesis. To better understand Polycomb biology, we profile the proximal interactome (proxeome) of multiple PRC1 and PRC2 subunits in mouse embryonic stem cells (mESCs). This analysis identifies >100 proteins proximal to PRC1 and PRC2, including transcription factors and RNA-binding proteins. Notably, approximately half of the PRC2 interactors overlap with PRC1. Pluripotency-associated factors, including NANOG, colocalize with PRC2 at specific genomic sites. Following PRC2 disruption, NANOG relocalizes to other genomic regions. Interestingly, we identify PRC1 members in PRC2 proxeomes but not reciprocally. This suggests that PRC1 and PRC2 may have independent functions in addition to their cooperative roles in establishing H3K27me3-marked chromatin domains. Finally, we compare PRC2 proxeomes across different cellular contexts, including ground-state mESCs, serum-cultured mESCs, and embryoid bodies. These analyses provide a comprehensive resource, enhancing our understanding of Polycomb biology and its dynamic role across developmental states.