Cell reports最新文献

The yeast Candida auris is an emerging pathogen. Understanding the molecular mechanisms of its uptake and processing by immune cells is thus critical for counteracting the spread of respective infections. We show that the phagocytosis of C. auris cells by primary human macrophages involves the formation of dot-like F-actin-rich structures at C. auris-containing phagosomes that we characterize as phagocytic podosomes. We analyze the composition, architecture, and dynamics of these structures, showing that they constitute a specific adaptation of the phagocytic actin network. The disruption of phagocytic podosomes is associated with reduced internalization of C. auris and delayed phagosomal maturation. Our data provide detailed insights into cytoskeletal rearrangements upon internalization of Candida by immune cells while also demonstrating that the actin network within phagocytic cups is not necessarily uniform and continuous. At the same time, we identify C. auris as a pathophysiologically relevant target whose internalization involves the formation of phagocytic podosomes.

Copy-number deletions in the 2p16.3/NRXN1 locus confer genetic risk for autism spectrum disorder (ASD) and schizophrenia (SCZ). Prior studies showed that heterozygous NRXN1 deletions reduce excitatory synaptic transmission in human induced pluripotent stem cell (iPSC)-derived cortical induced neurons, a phenotype also observed in SCZ patient lines carrying NRXN1 deletions. However, it remains unknown whether similar synaptic deficits exist in ASD patients with NRXN1 deletions. Clarifying this is important for determining whether NRXN1-deletion carriers should be approached uniformly or with consideration of disorder background, genetic modifiers, and deletion breakpoints. Here, we show that ASD-associated NRXN1 deletions alter cortical synaptic function in distinct ways. ASD deletions selectively enhance excitatory synaptic signaling without affecting inhibitory synapses, whereas SCZ deletions reduce both. At the network level, ASD deletions generate irregular firing patterns and impair homeostatic synaptic plasticity. Our study uncovers disorder-dependent synaptic mechanisms linked to NRXN1 deletions, providing a foundation for targeted therapeutic strategies for NRXN1-related disorders.

Affinity maturation and vaccine efficacy are compromised during chronic viral infections; however, underlying mechanisms remain unclear. Using the LCMV Cl13 model, we show that type I interferon (IFN-I) signaling in B cells plays a central role. IFN-I promotes early B cell activation but reduces clonal diversity and delays IgG1⁺ B cell entry into germinal centers (GCs), impairing high-affinity clone selection. Deletion of IFNAR1 in B cells partially restores nitrophenyl (NP)-specific IGHV1-72 and GC access but fails to rescue affinity maturation, suggesting a contribution of extrinsic factors. Somatic hypermutation is elevated in LCMV IFNAR1^+/+ and IFNAR1^-/- genotypes, though slightly less in IFNAR1^-/- B cells. BASELINe analysis indicates weaker selection pressure in complementarity determining regions (CDRs), reflecting impaired affinity-based selection, correlating with a reduced follicular regulatory T cells/follicular helper T cells (TFR/TFH) ratio. Our results show that intrinsic and extrinsic IFN-I-dependent mechanisms synergize to disrupt B cell fate, establishing IFN-I as a key regulator of humoral immunity and highlighting mechanisms underlying poor vaccine response during persistent viral infection.

Tendon injuries are common and heal poorly, whereas developing tendons repair with minimal scarring; how this capacity declines with age remains poorly understood. Here, we combine histology, single-nucleus, single-cell, and spatial transcriptomic profiling of human Achilles and quadriceps tendons across embryonic, fetal, and adult stages, including ruptured adult tendons. We identify seven embryonic progenitor states that are predicted to contribute to three tendon-associated lineages-fibrillar, connective tissue, and chondrogenic-which diversify over development, occupy discrete spatial niches, and appear to acquire specialized roles in matrix synthesis, remodeling, and mechanical adaptation. While non-fibroblast populations remain transcriptionally stable with age, fibroblasts undergo marked reprogramming, shifting to homeostatic or injury-responsive states. In ruptured adult tendons, a subset of fibroblasts partially reactivates developmental programs yet remains transcriptionally distinct from developmental states that exhibit scarless healing. These findings define the cellular architecture of human tendon development and aging and reveal lineage-specific targets for therapeutic repair.

Moral inconsistency-misaligning one's behavior with the same moral principle of judging others-undermines personal reputations and social relationships. This study explores the neural underpinnings of moral inconsistency in a profit-honesty trade-off setting with functional magnetic resonance imaging and transcranial temporal interference stimulation (tTIS). Experiment 1 demonstrated that participants showed inconsistent sensitivity to profit and honesty between moral behavior and moral judgment tasks. Furthermore, multivariate pattern analyses showed that participants with higher moral inconsistency exhibited reduced judge score representation across tasks and weaker connectedness during the moral behavior task in the ventromedial prefrontal cortex (vmPFC). Experiment 2 showed that tTIS modulation of the vmPFC increased moral inconsistency. These findings indicate the vmPFC's involvement in the neural basis of moral inconsistency. While individuals with higher moral inconsistency may be aware of moral principles when making decisions, they consider moral principles less and do not integrate them into their own behaviors.

TDP-43 pathology defines limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) and frequently co-occurs with Alzheimer's disease neuropathologic change (ADNC), yet the molecular consequences of overlapping pathology remain unclear. We performed biochemical and proteomic analyses of postmortem hippocampal tissue from 90 individuals spanning control, LATE-NC, ADNC, and ADNC+LATE-NC groups. Cryptic exon (CE) inclusion was quantified across eight TDP-43-regulated transcripts and related to phosphorylated TDP-43 (pTDP-43), amyloid, and tau pathology. ADNC+LATE-NC cases showed the highest CE levels. Although CE inclusion correlated with pTDP-43, CE measures were more strongly intercorrelated and defined low, intermediate, and high CE subtypes largely independent of amyloid and tau. Proteome-wide analyses revealed reduced abundance of CE-target proteins and disruption of synaptic, endosomal, and RNA-binding pathways in high CE cases. These signatures overlapped with changes in TDP-43-depleted human i³Neurons, supporting biological relevance. Overall, CE burden provides a robust molecular classifier of TDP-43 dysfunction across LATE-NC and ADNC.

Glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin hormone, and pharmacologic modulation of central GIP receptors (GIPRs) improves energy homeostasis and prevents conditioned taste avoidance (CTA). However, the mechanisms by which GIPR signaling impact food intake and aversion are incompletely understood. Here, we show that GIPR agonism abrogates the aversive and enhances the anorexigenic effects of the pro-inflammatory cytokine interleukin-1β (IL-1β). Aversion-encoding parabrachial calcitonin gene-related peptide (CGRP) neurons were required for IL-1β-induced CTA but not anorexia. Moreover, systemic IL-1β increased CGRP neural activity in vivo, and this was significantly attenuated by co-administration of a GIPR agonist. By contrast, GIPR in the dorsal vagal complex was required for the acute anorectic effect of GIPR agonism but not its anti-aversive effect. Taken together, our data suggest that GIPR agonism reduces food intake and prevents aversion via distinct circuits and that GIPR agonism may represent an effective approach to alleviate inflammation-induced aversion.

Liver cancer is a leading cause of cancer-related death due to the shortage of effective therapies, and MYC overexpression defines an aggressive and difficult-to-treat subset of patients. Given MYC's ability to reprogram cancer metabolism and the liver's role in coordinating systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited liver tumorigenesis. In vivo isotope tracing identified alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle and biosynthesis. Finally, treating a MYC-driven liver tumor model with L-cycloserine diminished the frequency of mouse tumor formation and attenuated the growth of established human liver tumors. Thus, we identify a targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.

Calcium signatures are key responses to diverse environmental stresses, yet how distinct calcium signals within confined subcellular compartments are decoded remains poorly understood. Calmodulin proteins, serving as canonical calcium sensors, play a vital role in downstream signaling. Notably, plants uniquely possess calmodulin-like (CML) proteins that contain EF-hand motifs and may function as specialized calcium sensors. Here, we find that CML49 and CML50, both of which contain EF-hands and intrinsically disordered regions (IDRs), contribute to pathogen resistance by forming molecular condensates. Pathogen-associated molecular pattern (PAMP) perception induces nuclear calcium signals that promote CML49 and CML50 condensate formation in an EF-hand- and IDR-dependent manner. These condensates sequester the WRKY11/17 transcription factors, thereby suppressing their immune-inhibitory activity. Our findings indicate that CML49/50-mediated condensate assembly spatially silences negative regulators and provides a mechanism for decoding nuclear calcium dynamics to activate plant immune responses.

Coronaviruses (CoVs) constitute a major global health threat, and their replication is inseparable from host factors. Investigating host-virus interactions is critical for elucidating the CoV life cycle. Here, we identify alpha-1,3-glucosyltransferase (ALG6) as an essential host factor for CoV replication. Mechanistically, its catalytic activity governs transmissible gastroenteritis virus (TGEV) replication, and ALG6 knockout (KO) inhibits viral entry by downregulating the receptor aminopeptidase N (ANPEP). Moreover, our results indicate that ALG6 KO triggers endoplasmic reticulum (ER) stress, resulting in suppressed viral replication. Further investigations demonstrate that ALG6 KO predominantly hinders viral replication by triggering downstream autophagy induced by ER stress. Transmission electron microscopy analysis reveals that ALG6 KO disrupts the formation of double-membrane vesicles (DMVs) during the initial stages of viral replication. In summary, our findings underscore the crucial role of ALG6 in the replication of CoVs, presenting a promising avenue for the development of potential therapeutic strategies against future CoV infections.