Cell reports最新文献

Axon degeneration is a key pathological feature in neural injuries and neurological disorders. MEK1/2 inhibitors (MEKis) are used in cancer therapy but can cause peripheral nerve lesions. Paradoxically, they are being considered for neurodegenerative diseases. Here, we show that MEK inhibition enhances, whereas its activation protects against, injury- or chemotherapy-induced axon degeneration in mouse DRG neurons. Mechanistically, the Raf-MEK-ERK cascade upregulates the critical axon survival factor Nmnat2 via ERK phosphorylation-dependent transcription. The MEKi trametinib decreases Nmnat2 expression and induces axon degeneration in DRG neurons, which is rescued by Nmnat2 overexpression. In contrast, cortical and spinal neurons maintain Nmnat2 transcription via CREB, independent of MEK-ERK, and are resistant to trametinib. Our findings demonstrate a neuron subtype-specific mechanism whereby MEK-ERK promotes axon stability through Nmnat2 upregulation. This context-dependent axon survival paradigm helps explain the vulnerability of PNS neurons to MEKi-induced axon degeneration, highlighting Nmnat2 as a potential target to counteract MEKi-associated neuropathy.

Wild freshwater fish microbiomes remain underexplored despite their ecological and economic importance. Through metagenomic sequencing of 903 gut/skin samples from 121 species in southwest China, we constructed the Wild Freshwater Fish Microbiome Catalog, comprising 705 metagenome-assembled genomes and 3,271 viral operational taxonomic units). Host phylogeny dominates microbial community variation, explaining 48.2% (skin) and 22.28% (gut) of the variation. Significant phylosymbiosis occurs in wild freshwater fish, particularly Cyprinidae, with a stronger skin than gut signal. Deterministic selection underpins phylosymbiosis via host-specific ecological filtering. Lifestyle factors (diet, living water layer) and geographical location also impact microbial communities. Notably, wild freshwater fish microbiota harbor a complete set of vitamin B₁₂de novo biosynthesis genes, with Cetobacterium as a keystone genus with probiotic potential. Our work expands gut and skin microbial genome resources, reveals host-microbe coevolution in freshwater fishes, and provides probiotic resources for aquaculture.

We identified poly(ADP-ribose) polymerase 7 (PARP7), a mono(ADP-ribosyl) transferase, as a regulator of C/EBPβ-dependent proadipogenic gene expression. PARP7 functions as a nuclear NAD⁺ sensor; at higher nuclear NAD⁺ concentrations in undifferentiated preadipocytes, PARP7 is catalytically active for auto-mono(ADP-ribosyl)ation (autoMARylation). As nuclear NAD⁺ concentrations decline upon differentiation, autoMARylation decreases dramatically. AutoMARylation promotes instability of PARP7 through an E3 ligase-ubiquitin-proteasome pathway mediated by the ubiquitin E3 ligases DTX2 and RNF114, which ubiquitylate MARylated PARP7. Stabilized PARP7 serves as a coregulator of C/EBPβ by stimulating p300-mediated histone H3 lysine 27 acetylation and the binding of C/EBPβ across the genome. Genetic depletion of PARP7 in mice promotes decreased body weight in mice fed a high-fat diet, reduced fat mass, inhibition of adipogenesis during mammary gland involution, and a reduction in lipid synthesis. Collectively, our results extend the biology of PARP7 to adipogenesis and elucidate the molecular mechanisms underlying a PARP7-p300-H3K27ac-C/EBPβ pathway for proadipogenic gene regulation.

Electrical stimulation at cellular resolution to restore the function of neural circuits is limited by the density of available electrode arrays. Although current steering with multi-electrode stimulation can be used to target cells between electrodes, it has not been proven for systematically targeting individual cells. We develop a framework for cellular-resolution current steering, leveraging the biophysics of electrically evoked spike generation, and test its efficacy in isolated macaque and human retina. Currents were passed through three electrodes simultaneously using large-scale high-density microelectrode arrays, directly evoking single spikes in retinal ganglion cells. The currents combined either linearly or nonlinearly to drive spiking, depending on the geometry of the electrodes relative to the cell. These findings were captured by a biophysical model and by a simpler parametric model in which spikes can initiate at several sites on the cell membrane and were leveraged to efficiently identify multi-electrode stimulation patterns that optimized cellular selectivity.

Cytokines and their receptors play important roles in brain development and aging-related disease, but their functions within the healthy adult brain remain poorly understood. Here, we show that pyramidal neurons in hippocampal CA1 induce Fn14 expression in response to activity and environmental enrichment. Once expressed, Fn14 dampens the activity of these neurons most prominently at the daily transition between light and dark. Fn14 expression in CA1 neurons is regulated by the circadian transcription factor Bmal1, and mice lacking Fn14 exhibit disrupted sleep-wake patterns in vivo. At the cellular level, microglia contact fewer excitatory synapses in the absence of Fn14, while neuronal overexpression of Fn14 induces rod-like microglia and recruits them to excitatory synapses. Beyond a homeostatic context, mice lacking Fn14 exhibit heightened susceptibility to chemically induced seizures. These findings reveal that pro-inflammatory cytokine receptors such as Fn14 can play major roles in healthy neurological function in the adult brain.

The human gut-liver axis is a critical immunological interface, yet factors that shape T cell adaptation and clonal expansion across tissues remain unclear. We performed integrated single-cell RNA and T cell receptor sequencing on T cells from matched colon epithelium, lamina propria, liver, and blood of the same donors, enabling clonal tracking and tissue-specific transcriptional profiling without inter-individual confounders. Colonic intraepithelial lymphocytes were largely clonally distinct from lamina propria T cells. Tissue-resident T cells in colon vs. liver displayed marked transcriptional divergence, with colonic lamina propria tissue-resident memory T cells (TRMs) enriched for interferon-stimulated genes (e.g., ISG15 and IFITM3). Ligand-receptor analysis implicated liver-derived factors, including fibrinogen gamma chain, in shaping colon TRM states. Across tissues, highly expanded clones of the same cell type shared a core upregulated gene set, suggesting common determinants of clonal success. These data provide a same-donor single-cell atlas of T cell diversity and adaptation across the human gut-liver-blood axis.

Autophagy is a highly conserved cellular process in which cytoplasmic contents are sequestrated by autophagosomes and delivered to lysosomes for degradation. Generation of degradative autolysosomes mediated by SNARE proteins is essential; however, the regulatory mechanisms governing this process remain underexplored. This study aimed to demonstrate that E3 ubiquitin ligase HRD1 regulates liquid-liquid phase separation (LLPS) of SNAP29, thereby modulating SNARE assembly. We found that HRD1 deficiency enhances autophagy activity and promotes autolysosome formation in a SNAP29-dependent manner. We also determined that SNAP29 forms highly dynamic condensates in in vivo and in vitro, which are crucial for the assembly of the SNARE complex. Mechanistically, HRD1 interacts with SNAP29 to suppress its condensation, whereas HRD1 depletion accelerates both SNAP29 condensate formation and SNARE complex assembly. Our findings reveal that HRD1 acts as a negative regulator in autolysosome formation by interacting with SNAP29, inhibiting its LLPS process, thereby modulating the binding affinity among SNARE components.

Each year, influenza A virus (IAV) infection of the lung causes half a million deaths worldwide. Patients with compromised immunity experience distinct influenza pathogenesis; however, most IAV-related research is done with wild-type mice or people who are otherwise healthy. We utilize a model of immunocompromised recombination-activating gene 1 (Rag1)-knockout (KO) mice to discover natural killer (NK) cell activation and regulation mechanisms during IAV infection. The treatment of IAV-challenged Rag1-KO mice with a monoclonal antibody (mAb) targeting programmed death ligand 1 (PD-L1) triggers NK cell-intrinsic signaling of PD-L1 and significantly delays lethality. This treatment upregulates tumor necrosis factor-related apoptosis-inducing ligand on NK cells downstream of PD-L1 signaling and is required for the benefits of PD-L1 mAb treatment in IAV-challenged Rag1-KO mice. These results present a paradigm shift for understanding the innate immune response to respiratory virus infections, offering an alternative approach for therapeutic treatment of IAV infections in patients with compromised immunity.

Broadly neutralizing antibodies (bNAbs) targeting multiple sites of HIV-1 Env vulnerability can be induced by infection, but simultaneous elicitation of bNAbs against multiple epitopes has not been achieved by vaccination. In this study, we designed a dual-epitope vaccine targeting both the fusion peptide (FP) and the V2 apex and evaluated its capacity to induce bNAbs against both epitopes in rhesus macaques. This vaccine combined an FP conjugate with a cocktail of engineered Env trimers with enhanced V2 apex recognition and increased antigen retention in lymph nodes. Macaque immunization with the dual-epitope vaccine elicited >1,000-fold higher autologous tier 2-neutralizing titers than wild-type Env trimers and enhanced heterologous neutralization. Both FP- and V2 apex-monoclonal antibodies were isolated from immunized macaques and showed heterologous neutralization with genetic and structural signatures similar to well-characterized FP and V2 apex bNAbs. These results demonstrate proof of concept for simultaneous vaccine elicitation of neutralizing antibodies against multiple sites of Env vulnerability.

The ability to switch behavioral states is essential for animals to adapt and survive. Here, we demonstrate how norepinephrine (NE) activation of radial astrocytes alters visual processing in the optic tectum (OT) of developing Xenopus laevis. NE activates calcium transients in radial astrocytes through α1-adrenergic receptors. NE and radial astrocyte activation shift OT response selectivity to preferentially respond to looming stimuli, associated with predation threat. NE-mediated astrocytic release of ATP/adenosine reduces excitatory transmission by retinal ganglion cell axons, without affecting inhibitory transmission in the OT. Blockade of adenosine receptors prevents both decreased neurotransmission and the selectivity shift. Chemogenetic activation of tectal radial astrocytes mimics NE's effects and enhances behavioral detection of looming stimuli in freely swimming animals, whereas chelating calcium in astrocytes to block transients prevents the selectivity shift. NE signaling via radial astrocytes improves network signal-to-noise for detecting threatening stimuli, with important implications for sensory processing and behavior.