Communications Biology最新文献

Hypoxia-inducible factors (HIFs) are key regulators of intracellular oxygen homeostasis. The marked increase in HIFs activity in hypoxia as compared to normoxia, together with their transcriptional control of primary metabolic pathways, motivated the widespread view of HIFs as responsible for the cell's metabolic adaptation to hypoxic stress. In this work, we suggest that this prevailing model of HIFs regulation is misleading. We propose an alternative model focused on understanding the dynamics of HIFs' activity within its physiological context. Our model suggests that HIFs would not respond to but rather prevent the onset of hypoxic stress by regulating the traffic of electrons between catabolic substrates and oxygen. The explanatory power of our approach is patent in its interpretation of the Warburg effect, the tendency of tumor cells to favor anaerobic metabolism over respiration, even in fully aerobic conditions. This puzzling behavior is currently considered as an anomalous metabolic deviation. Our model predicts the Warburg effect as the expected homeostatic response of tumor cells to the abnormal increase in metabolic demand that characterizes malignant phenotypes. This alternative perspective prompts a redefinition of HIFs' function and underscores the need to explicitly consider the cell's metabolic activity in understanding its responses to changes in oxygen availability.

Transcription Factor EB (TFEB) controls lysosomal biogenesis and autophagy in response to nutritional status and other stress factors. Although its regulation by nuclear translocation is known to involve a complex network of well-studied regulatory processes, the precise contribution of each of these mechanisms is unclear. Using microfluidics technology and real-time imaging coupled with mathematical modelling, we explored the dynamic regulation of TFEB under different conditions. We found that TFEB nuclear translocation upon nutrient deprivation happens in two phases: a fast one characterised by a transient boost in TFEB dephosphorylation dependent on transient calcium release mediated by mucolipin 1 (MCOLN1) followed by activation of the Calcineurin phosphatase, and a slower one driven by inhibition of mTORC1-dependent phosphorylation of TFEB. Upon refeeding, TFEB cytoplasmic relocalisation kinetics are determined by Exportin 1 (XPO1). Collectively, our results show how different mechanisms interact to regulate TFEB activation and the power of microfluidics and quantitative modelling to elucidate complex biological mechanisms.

Forbs ("wildflowers") are important contributors to grassland biodiversity but are vulnerable to environmental changes. In a factorial experiment at 94 sites on 6 continents, we test the global generality of several broad predictions: (1) Forb cover and richness decline under nutrient enrichment, particularly nitrogen enrichment. (2) Forb cover and richness increase under herbivory by large mammals. (3) Forb richness and cover are less affected by nutrient enrichment and herbivory in more arid climates, because water limitation reduces the impacts of competition with grasses. (4) Forb families will respond differently to nutrient enrichment and mammalian herbivory due to differences in nutrient requirements. We find strong evidence for the first, partial support for the second, no support for the third, and support for the fourth prediction. Our results underscore that anthropogenic nitrogen addition is a major threat to grassland forbs, but grazing under high herbivore intensity can offset these nutrient effects.

During human immunodeficiency virus (HIV-1) entry, the metastable pretriggered envelope glycoprotein (Env) trimer ((gp120/gp41)₃) opens asymmetrically. We present cryo-EM structures of cleaved asymmetric Env trimers in amphipol-lipid nanodiscs. The gp41 membrane-proximal external region (MPER) could be traced in Env protomers that remained close to the nanodisc despite Env tilting. The MPER interacts with the gp120 C-termini and gp41 α9 helices at the base of the Env trimer. MPER conformation is coupled with the tilt angles of the α9 helices, the helicity of the gp41 heptad repeat (HR1_N) regions, and the opening angles between the protomers of the asymmetric trimers. Our structural models explain the stabilizing effects of MPER integrity and Env proteolytic maturation on the pretriggered Env conformation. Superimposed on the asymmetry of the Env protomers, variation in the glycans at the trimer apex creates substantial structural heterogeneity in the V2 quaternary epitopes of difficult-to-elicit broadly neutralizing antibodies.

Drosophila P75 (dP75), a homolog of the human LEDGF/p75, is crucial for oogenesis by recruiting the histone kinase Jil-1 to euchromatin and impeding H3K9me2 spreading. Like LEDGF, dP75 binds transcriptionally active chromatin, but its precise mechanism remains unclear. Here we show that its PWWP domain prefers binding to thymidine-rich DNA over GC-rich sequences. Crystal structures both in apo and ssDNA-bound states, reveal a domain-swapped homodimer. The aromatic cage, known to recognize histone methyllysine, also engages thymine. Mutations in this cage mimic dP75 knockout phenotypes, including impaired chromatin binding, transposon upregulation, and female sterility. Although dP75 maintains chromatin-bound in H3K36A mutant flies, alterations in the aromatic cage disrupt this localization, underscoring its role in DNA binding. These findings reveal how dP75 targets euchromatin through a PWWP domain that integrates histone reading and nucleotide recognition, advancing our understanding of PWWP domains.

Myocardial infarction (MI) compromises the cardiac microvascular endothelial barrier, increasing leakage and inflammation. HIF2α, predominantly expressed in cardiac endothelial cells during ischemia, has an unclear role in barrier function during MI. Here, we show that inducible, adult endothelial-specific deletion of Hif2α in mice leads to increased mortality, cardiac leakage, inflammation, reduced heart function, and adverse remodeling after MI. In parallel, human cardiac microvascular endothelial cells (HCMVECs) lacking HIF2α display impaired barrier integrity, reduced tight-junction proteins, increased cell death, and elevated IL-6 levels, effects that are alleviated by overexpressing ARNT, a key partner of HIF2α under hypoxic conditions. Interestingly, ARNT, but not HIF2α, directly binds the IL-6 promoter to suppress its expression. These findings suggest the HIF2α/ARNT axis as a protective mechanism in heart failure post-MI and identify potential therapeutic targets to support cardiac function.

Large-scale GWAS studies have uncovered hundreds of genomic loci linked to facial and brain shape variation, but only tens associated with cranial vault shape, a largely overlooked aspect of the craniofacial complex. Surrounding the neocortex, the cranial vault plays a central role during craniofacial development and understanding its genetics are pivotal for understanding craniofacial conditions. Experimental biology and prior genetic studies have generated a wealth of knowledge that presents opportunities to aid further genetic discovery efforts. Here, we use the conditional FDR method to leverage GWAS data of facial shape, brain shape, and bone mineral density to enhance SNP discovery for cranial vault shape. This approach identified 120 independent genomic loci at 1% FDR, nearly tripling the number discovered through unconditioned analysis and implicating crucial craniofacial transcription factors and signaling pathways. These results significantly advance our genetic understanding of cranial vault shape and craniofacial development more broadly.

Phenological mismatches and resource limitations resulting from ongoing environmental change can have severe impacts on pollinator fitness. Recent findings show that bumblebee workers respond to pollen scarcity by damaging plant leaves in ways that can accelerate flowering, suggesting a mechanism by which direct information transfer from bees to plants might influence the timing of flower production. However, the ecological and adaptive significance of this interaction remains uncertain. Here we report that mated and unmated queens of Bombus terrestris also damage leaves, with similar effects on flowering. Furthermore, we document leaf damage by wild-caught queens from 12 species, spanning seven subgenera, indicating damaging behavior is widespread among Bombus species. Leaf damage by bumblebee queens may have particular relevance in the context of colony founding and early development, where the timely availability of local floral resources can be critical for colony success and fitness.

Identifying genetic dependencies in human colon cancer could help identify effective treatment strategies. Genome-wide CRISPR-Cas9 dropout screens have the potential to reveal genetic dependencies, some of which could be exploited as therapeutic targets using existing drugs. In this study, we comprehensively characterized genetic dependencies present in a colon cancer organoid avatar, and validated tumor-specific selectivity of select pharmacologic agents. We conducted a genome-wide CRISPR dropout screen to elucidate the genetic dependencies that interacted with select driver somatic mutations. We found distinct genetic dependencies that interacted with WNT, MAPK, PI3K, TP53, and mismatch repair pathways and validated targets that could be exploited as treatments for this specific subtype of colon cancer. These findings demonstrate the utility of functional genomic screening in the context of personalized medicine.

The capacity of photosynthetic microorganisms to fix carbon dioxide into biomass positions them as promising cell factories for sustainable biomanufacturing. However, limitations in screening throughput hinder the identification of enzymes, strains, and growth conditions needed to realize this potential. Here we present a microplate-based high-throughput cultivation system that can be integrated into existing automation infrastructure and supports growth of both prokaryotic and eukaryotic photosynthetic microorganisms. We validate this system by optimizing BG-11 medium compositions for Synechococcus elongatus UTEX 2973, Chlamydomonas reinhardtii UTEX 90 and Nostoc hatei CUBC1040, resulting in growth rates increases of 38.4% to 61.6%. We also identify small molecules that influence growth rates in Synechococcus elongatus UTEX 2973, including candidate compounds for growth rate increase and dozens that prevent growth. The sensitivity, throughput, and extensibility of this system support screening, strain isolation, and growth optimization needed for the development of photosynthetic microbial cell factories.