Cell reports最新文献

Despite recent advances in cell migration mechanics, the principles governing rapid T cell movement remain unclear. Efficient migration is critical for antitumoral T cells to locate and eliminate cancer cells. To investigate the upper limits of cell speed, we develop a hybrid stochastic-mean field model of bleb-based cell motility. Our model suggests that cell-matrix adhesion-free bleb migration is highly inefficient, challenging the feasibility of adhesion-independent migration as a primary fast mode. Instead, we show that T cells can achieve rapid migration by combining bleb formation with adhesion-based forces. Supporting our predictions, three-dimensional gel experiments confirm that T cells migrate significantly faster under adherent conditions than in adhesion-free environments. These findings highlight the mechanical constraints of T cell motility and suggest that controlled modulation of tissue adhesion could enhance immune cell infiltration into tumors. Our work provides insights into optimizing T cell-based immunotherapies and underscores that indiscriminate antifibrotic treatments may hinder infiltration.

Neuro-glial mitochondrial transfer critically sustains neuronal function in disease. While this transfer reshapes inflammatory microenvironments, its pathological mechanisms in peripheral inflammatory pain remain uncharacterized, impeding targeted interventions. Here, employing primary satellite glial cells (SGCs)-trigeminal ganglion neurons (TGNs) co-culture models, we demonstrate that, during acute inflammation, SGCs transfer functional mitochondria to injured TGNs via tunneling nanotubes and free mitochondrial uptake. Inflammatory stress impairs mitophagy, leading to dysfunctional mitochondrial accumulation and heightened neuronal hyperexcitability. Mitochondria from SGCs restore mitophagic flux and enhance mitochondrial-endoplasmic reticulum (ER) contact sites, thereby facilitating calcium exchange and homeostasis while reducing neuronal hyperexcitability. Critically, Atl1 knockout and overexpression mice models reveal that ATL1-driven ER restructuring initiates autophagosome formation during mitophagy and regulates early-stage autophagic progression. Taken together, our findings uncover a neuroprotective axis wherein glial mitochondrial donation safeguards neurons, directly nominating mitochondrial dynamics for therapeutic intervention in orofacial inflammatory pain.

Oscillations in the levels of second messengers are observed throughout the phylogenetic tree, with signaling information encoded in the frequency of the spikes. Different biological targets respond to different frequencies of oscillation, leading to the concept of frequency counting. The most widely observed and best understood oscillatory second messenger is cytosolic Ca²⁺. Ca²⁺ oscillations are generated in all cell types, are seen throughout the life of a cell, and are indispensable for diverse biological processes ranging from fertilization to cell death and myriad responses in between including excitation-transcription coupling through Ca²⁺-dependent gene expression. The widely expressed Ca²⁺-dependent transcription factors nuclear factor (NF) of activated T cells (NFAT) and NF-κB are recruited by different Ca²⁺ oscillation frequencies, increasing the signaling bandwidth through the universal Ca²⁺ messenger. Here, we show that Ca²⁺ nanodomains near Ca²⁺ channels at the cell surface are central to gene expression. Cytosolic Ca²⁺ oscillations are not necessary for Ca²⁺-dependent gene expression, provided Ca²⁺ nanodomains near Ca²⁺ release-activated Ca²⁺ (CRAC) channels are formed. Our results establish that a fundamental unit of excitation-transcription coupling is the Ca²⁺ channel nanodomain at the cell surface.

Human early development is challenging to study due to limited samples and cell numbers. The emergence of 8-cell-stage (8C) embryo-like cells (8CLCs) offers new opportunities to understand embryonic genome activation (EGA) in humans. Our research compares and characterizes 8CLCs from various stem cell-based systems to determine how well these models reflect human early embryonic development. Using single-cell RNA sequencing datasets from multiple studies, we integrate data to identify key gene co-expression modules, transposable element expression, and biological processes recapitulated in 8CLCs. We identify both mature and intermediate 8CLCs, with the Yoshihara and Mazid datasets best representing 8C embryos. 8CLCs show remodeling in energy and RNA metabolism, regulation of RNA splicing, and ribosome biogenesis, mirroring human 8C embryos. Our findings underscore the importance of distinguishing mature 8CLCs from partially reprogrammed cell states to improve their use as models for human EGA.

Cytoplasmic dynein drives minus-end-directed transport along microtubules, a process critically modulated by Lis1. Although Lis1 has been reported to both inhibit and activate dynein, the molecular basis for these opposing effects remains unclear. We identify the COP9 signalosome (CSN) and protein arginine methyltransferase 5 (PRMT5) complexes as key determinants of Lis1-dependent dynein regulation. Lis1 recruits CSN to dynein, promoting deneddylation and maintaining the motor in an inactive state, thus functioning as an off switch. Neddylation of dynein intermediate chain 1 (DIC1) at K42 is required for the assembly of active transport complexes. In contrast, PRMT5 methylates Lis1 at R238, switching Lis1 to a positive regulator. This modification displaces CSN from dynein, restores neddylation, and promotes motor activation and cargo transport. These findings reveal a dual regulatory axis in which Lis1 integrates CSN- and PRMT5-dependent cues to switch dynein between inactive and active states, providing a mechanistic basis for Lis1's contrasting roles in dynein control.

Bacillus methanolicus, a unique plasmid-dependent and thermophilic methylotroph, is an ideal chassis for one-carbon (C1) biomanufacturing. Despite its evolutionary uniqueness and industrial promise, the synthetic biology toolkit remains limited in comparison to that of conventional model microorganisms. Here, we present a comprehensive toolkit comprising a high-efficiency electroporation protocol, a CRISPR-Cas9 method enabling robust and multiplex genome editing, diverse neutral loci for gene integration, and a cloud-based genome-scale metabolic model iBM822 for user-friendly biodesign. Leveraging this toolkit, we systematically dissected plasmid-dependent methylotrophy, restriction-modification machinery, and the functional significance of chromosomal methylotrophic genes. To address plasmid loss-induced strain degeneration, we integrated the large endogenous plasmid pBM19 into the chromosome for stable and intact methylotrophic growth. Finally, by integrating metabolic modeling with CRISPR-Cas9 editing, we engineered L-arginine feedback regulation to achieve L-arginine overproduction from methanol. This study establishes a synthetic biology framework for B. methanolicus, promoting mechanistic exploration of methylotrophy and C1 biomanufacturing.

TRPV1, a member of the transient receptor potential vanilloid subfamily, mediates nociception and thermoregulation. TRPV1-targeting analgesics frequently induce hyperthermia, underscoring the need for structural insights to guide the development of safer compounds. Here, we determined the structures of rat TRPV1 bound to the clinical candidate analgesics AMG517, AMG9810, and SB366791. AMG517 and AMG9810 are deeply situated within the S3-S4 interface of the vanilloid pocket, where they interact with residues from the S3-S6 helices, as well as the S4-S5 linker. These interactions induce local deformations in the TRP-box and lower S6 helix, accompanied by a modest rotation of the S1-S4 bundle, leading to partial dilation of the lower gate. The distinct allosteric changes of AMG517 and AMG9810, compared with the non-hyperthermic ligand SB366791, suggest a structural basis by which TRPV1-targeting analgesics influence thermoregulation and provide insights for designing safer analogs.

Osteoarthritis (OA) is a prevalent age-related joint disorder with limited treatment options. Chronic activation of the innate immune response in chondrocytes plays a key role in OA progression. However, the underlying mechanisms remain incompletely understood. Here, we report that mitochondrial antiviral signaling protein (MAVS) exacerbates cartilage extracellular matrix (ECM) degradation in OA. MAVS activation is observed in chondrocytes from both OA patients and the destabilization of the medial meniscus (DMM) mouse model. Both constitutive and chondrocyte-specific MAVS knockout alleviate cartilage degradation, osteophyte formation, subchondral bone remodeling, and synovitis in DMM mice. Conversely, MAVS overexpression aggravates these OA phenotypes. Mechanistically, cytosolic accumulation of mitochondrial double-stranded RNA in chondrocytes triggers MAVS activation, leading to MAVS-nuclear factor κB-dependent ECM degradation by inducing matrix metalloproteinase 3 (MMP3) and MMP13. Pharmacologically blocking MAVS using L-lactate significantly attenuates ECM degradation and OA progression. These findings suggest that MAVS signaling is critical in OA pathogenesis and may be a potential therapeutic target for OA treatment.

Skilled fine movements are essential for daily life. Although prior work has identified motor cortical tuning to low-level kinematic features like velocity and position, these findings fall short of explaining the precision underlying complex motor behaviors. Critically, it remains unclear whether and how the motor cortex (MC) represents higher-level features of movement. Using single-unit recordings from the human MC during handwriting, we employed surrogate deep neural networks (DNNs) as a tool to investigate these mechanisms. We found that surrogate DNNs capture key aspects of neural activity at both single-unit and population levels. Through this approach, we demonstrate that the MC encodes hierarchical information of movement, including both low-level kinematics and high-level features related to the written content. These results uncover neural encoding behind dexterous motor execution and provide a framework for studying the neural basis of complex behavior.

The identities of primary afferents transducing mechanical allodynia following nerve injury remain unclear. We genetically label brushing-activated (BA) trigeminal ganglia (TG) neurons using Fos^CreER mice with trigeminal nerve injury (TNI). BA TG neurons are largely medium-sized. Many express neurofilament200 and Ntrk3, markers for low-threshold mechanoreceptors, with lower co-localization with nociceptor markers such as Calca or Trpv1. Chemogenetic inhibition of BA TG neurons reduces mechanical allodynia, whereas their chemogenetic activation increases spontaneous face wiping after TNI. Brushing-induced conditional knockdown (bcKD) of Piezo2 from BA TG afferents reduces punctate and dynamic mechanical allodynia. In vivo TG GCaMP Ca²⁺ imaging shows that Piezo2 bcKD reduces not only hypersensitivity to low-force mechanical stimulation, mostly among medium-sized neurons, but also, unexpectedly, TNI-induced spontaneous activity. Therefore, Fos is useful for genetic labeling and manipulation of BA TG neurons. Furthermore, innocuous mechanical stimuli activate multiple TG afferent subtypes after TNI, possibly accounting for the complexity of resulting painful symptoms.