PLoS Biology最新文献

CD8+ T cells are capable of specifically targeting and eliminating malignant tumor cells, but tumor cells can develop resistance mechanisms to escape CD8+ T cell-mediated killing. Here, we performed a whole genome CRISPR-Cas9 knockout screen under CD8+ T cells pressure and identified the E3 ubiquitin ligase CUL5 as an essential factor required for escaping CD8+ T cells killing in bladder cancer cells. We found that CUL5 knockout promoted the sensitivity of bladder cancer cells to CD8+ T cell-mediated killing both in vivo and in vitro. Mechanistically, CUL5 loss reduced the ubiquitination of PTBP1, which regulated alternative splicing of RUBCN pre-mRNA and led to an increase in the levels of the RUBCN-S isoform, thereby preventing immune evasion of bladder cancer cells by inhibiting autophagy. Importantly, CUL5 knockout significantly enhanced the efficacy of anti-PD-1 immunotherapy in a xenograft model. Collectively, these findings reveal a novel mechanism of bladder cancer immune evasion, providing potential targets for cancer immunotherapy.

Neuronal communication relies on neurotransmitter release from synaptic vesicles. The endocytic protein AP180 is critical for efficient vesicle recycling at presynaptic terminals, and its loss impairs neurotransmission, producing reduced release frequency, enlarged synaptic vesicles, and increased quantal amplitude. Yet how AP180 controls vesicle size and whether vesicle size influences release remains unclear. Here, we show that the C-terminal Assembly domain (AD) of AP180 determines vesicle size and thereby regulates release properties in Caenorhabditis elegans. An AP180 variant lacking the AD (AP180∆AD) increases release frequency, contrasting sharply with the reduced transmission in ap180 null mutants, yet fails to correct the vesicle size or quantal amplitude. These enlarged vesicles evade curvature-dependent inhibition by complexin, a presynaptic regulator of fusion, while remaining dependent on complexin for evoked responses. This selective escape reveals that vesicle size influences release dynamics through curvature-sensing proteins. Replacing the AP180 AD with actin-binding motifs restores normal vesicle size, quantal amplitude, and release frequency, indicating that actin interactions are both necessary and sufficient for AD function. Biochemically, we show that the intrinsically disordered AD forms condensates that enrich actin monomers and nucleate filament assembly, while full-length AP180 couples PIP2-rich membranes to actin filaments. Together, these findings reveal that the AP180 AD regulates synaptic vesicle size through actin binding, establishing vesicle morphology as a key influencer of curvature-dependent release control.

Macrophages are essential for host defense, yet how parenchyma-residing macrophages detect pathogens without direct contact remains unclear. Cryptococcus neoformans is an encapsulated fungal pathogen that infects the brain. Using in situ imaging of mouse model, we showed that brain-resident microglia vigilantly detect capillary-residing C. neoformans prior to its blood-brain barrier transmigration, but are less responsive to nonencapsulated fungi or parenchyma-injected C. neoformans. Microglia migrate to and enwrap leaky capillaries harboring fungi, leading to fungal uptake but not clearance, instead promoting fungal growth. Microglial response is triggered by released capsule components, rather than the assembled capsule. In particular, glucuronoxylomannan (GXM) plays a critical role by activating endothelial cells to release nucleotides which act on microglia P2Y12. Our findings revealed a novel paradigm by which microglia detect pathogens without direct contact, offering new insights for microglia-directed antifungal therapies.

The ability to anticipate rhythmic and melodic structures in music is considered a fundamental human trait, present across all cultures and predating linguistic comprehension in human development. Yet, it remains unclear the extent to which this ability is already developed at birth. Here, we used temporal response functions to assess rhythmic and melodic neural encoding in newborns (N = 49) exposed to classical monophonic musical pieces (real condition) and control stimuli with shuffled tones and inter-onset intervals (shuffled condition). We computationally quantified context-based rhythmic and melodic expectations and dissociated these high-level processes from low-level acoustic tracking, such as local changes in timing and pitch. We observed encoding of probabilistic rhythmic expectations only in response to real but not shuffled music. This proves newborns' ability to rely on rhythmic statistical regularities to generate musical expectations. We found no evidence for the tracking of melodic information, demonstrating a downweighting of this dimension compared to the rhythmic one. This study provides neurophysiological evidence that the capacity to track statistical regularities in music is present at birth and driven by rhythm. Melodic tracking, in contrast, may receive more weight through development with exposure to signals relevant to communication, such as speech and music.

Bargaining is a fundamental social behavior in which individuals often accept unfair offers. Traditional behavioral models, based solely on choice data, typically interpret such acceptance as simple reward-maximization. However, regulating inequity aversion may also play a critical role in these decisions. Incorporating response time alongside choice data allows us to quantify participants' internal mental effort when deciding to accept unfair offers. We conducted functional magnetic resonance imaging (fMRI) while participants played the ultimatum game, deciding within 10 s whether to accept or reject monetary offers from a proposer. Using the drift diffusion model (DDM), we quantified decision-making dynamics based on both choice and response time. Participants with lower levels of behavioral disadvantageous inequity (DI) aversion (reflected by a lower DDM weight for DI) showed stronger neural representations of DI in the dorsal anterior cingulate cortex (dACC). Functional connectivity analysis revealed a negative correlation between the dACC and bilateral ventrolateral prefrontal cortex (vlPFC) when DI was high. This connectivity predicted both rejection rates and response times associated with the acceptance of DI offers. Furthermore, robust linear regression showed that only dACC-vlPFC connectivity-not reward-related activity-explained both the rejection rates and response times. Finally, right vlPFC activity correlated with amygdala activity under high DI conditions. These findings suggest that the dACC plays a key role in regulating responses to DI, thereby facilitating the acceptance of unfair offers.

While clinical features of bacterial vaginosis have been amply described, its underlying causes are still debated. A new ecological model published in PLOS Biology provides a solid hypothesis corroborated by existing data, hinting at new prophylactic strategies.

The vaginal microbiota is associated with the health of women and newborns alike. Despite its comparatively simple composition relative to other human microbiota systems, the mechanisms underpinning the dynamics and stability of vaginal microbial communities remain elusive. A crucial, yet so far underexplored, aspect of vaginal microbiota ecology is the role played by nutritional resources. Glycogen and its derivatives, produced by vaginal epithelia, are accessible to all bacterial constituents of the microbiota. Concurrently, free sialic acid and fucose offer supplementary nutritional resources to bacterial strains capable of cleaving them from glycans, which are structurally integral to mucus. Notably, bacteria adept at sialic acid exploitation are often correlated with adverse clinical outcomes and are frequently implicated in bacterial vaginosis (BV). In this study, we introduce a novel mathematical model tailored to human vaginal microbiota dynamics to explore the interactions between bacteria and their respective nutritional landscape. Our resource-based model examines the impact of the relative availability of glycogen derivatives (accessible to all bacterial species) and sialic acid (exclusive to some BV-associated bacteria) on the composition of the vaginal microbiota. Our findings elucidate that the success of BV-associated bacteria is intricately linked to their exclusive access to specific nutritional resources. This private access fortifies communities dominated by BV-associated bacteria, rendering them resilient to compositional transitions. We empirically corroborate our model prediction with longitudinal clinical data on microbiota composition and previously unpublished metabolomic profiles obtained from a North American cohort. The insights gleaned from this study shed light on potential pathways for BV prevention and treatment.

Drug resistance is a critical challenge in treating life-threatening fungal infections. Here, we uncover a mechanism of acquired azole resistance in Candida albicans through mutations in CAP1, encoding a conserved fungal transcription factor that mediates the oxidative stress response. We analyzed 300 clinical isolates and identified 25 distinct CAP1 missense or nonsense mutations, with many occurring within the DNA-binding domain. We identified two nearly identical CAP1 heterozygous nonsense mutations, one in an isolate obtained from a bloodstream infection and one in a population of cells undergoing adaptation to fluconazole in vitro. Both CAP1 nonsense mutations resulted in loss of the C-terminal nuclear export signal, leading to nuclear retention of Cap1 and subsequent activation of genes associated with the oxidative stress response and drug transport. The CAP1 C-terminal truncations conferred significant fitness advantages in the presence of fluconazole, both in vitro and in a murine model of candidiasis. Strikingly, we discovered a therapeutic vulnerability: azole concentrations above the minimal inhibitory concentration were fungicidal to mutants with the CAP1 C-terminal truncation. The fungicidal effect was attributed to both elevated azole-induced reactive oxygen species and a compromised oxidative stress response in Cap1-truncated cells. Our results provide novel characterization of de novo CAP1 point mutations emerging in both laboratory and clinical contexts, elucidate the mechanisms underlying Cap1-regulated stress responses, and reveal a potential therapeutic target for overcoming drug resistance in C. albicans infections.

Oviposition holds crucial significance for insect reproduction. Nevertheless, the research on the neural conduction mechanism of oviposition is still rather limited in most agricultural pests. Here, we demonstrate that the conserved Kainate receptors (KARs) expressed in the glutamatergic neurons (GNs) and the ovipositor neuromuscular junctions (NMJs) regulate the oviposition behavior in Bactrocera dorsalis. We identified two KARs (Grik2b and Grik2c), which control the oviposition behavior by influencing both oviposition preference and egg-laying quantity. Protein-ligand interaction indicated that glutamate serves as the neurotransmitter of Grik2b and Grik2c. Knockdown glutamate-coding genes adversely impacted oviposition preference and egg-laying quantity. Specific knockdown Grik2b (or Grik2c) in the GNs and NMJs could respectively influence oviposition preference and egg-laying quantity. Finally, inhibitors of KARs were screened for their ability to inhibit oviposition. Our study provides strong supporting evidence that a novel neural conduction mechanism for oviposition by uncovering the diverse roles of KARs and provides potential molecular target controlling insect oviposition.

Hijacking of host DNA damage repair (DDR) pathways to facilitate virus replication is broadly conserved amongst diverse viral families. It has been well established that the HIV-1 accessory protein Vpr induces constitutive DDR signaling and G2/M cell cycle arrest, but the virologic function of this activity remains unclear. Here, we use a combination of functional, pharmacologic, biochemical, and genetic approaches to establish that virion-associated and de novo Vpr proteins induce DDR responses that trigger global epigenetic remodeling and activation of transcription programs to enhance HIV-1 promoter activity during acute infection and reactivation from latency. Functional, genetic, and bimolecular fluorescence complementation experiments reveal that Vpr segregates into two functionally discrete pools-a multimeric pool in the nucleus associated with chromatin and a monomeric pool in the cytoplasm associated with a host E3-ubiquitin ligase. Vpr-induced DDR and epigenetic remodeling activities are present in common HIV-1 subtypes circulating globally and in patient-derived isolates.