ISSN / EISSN : 15449173 / 15457885
Current Publisher: Public Library of Science (PLoS) (10.1371)
Total articles ≅ 5,373
Google Scholar h5-index: 87
Latest articles in this journal
PLOS Biology, Volume 17; doi:10.1371/journal.pbio.3000436
Abstract:Bats harbor many zoonotic viruses, including highly pathogenic viruses of humans and other mammals, but they are typically asymptomatic in bats. To further understand the antiviral immunity of bats, we screened and identified a series of bat major histocompatibility complex (MHC) I Ptal-N*01:01–binding peptides derived from four different bat-borne viruses, i.e., Hendra virus (HeV), Ebola virus (EBOV), Middle East respiratory syndrome coronavirus (MERS-CoV), and H17N10 influenza-like virus. The structures of Ptal-N*01:01 display unusual peptide presentation features in that the bat-specific 3–amino acid (aa) insertion enables the tight “surface anchoring” of the P1-Asp in pocket A of bat MHC I. As the classical primary anchoring positions, the B and F pockets of Ptal-N*01:01 also show unconventional conformations, which contribute to unusual peptide motifs and distinct peptide presentation. Notably, the features of bat MHC I may be shared by MHC I from various marsupials. Our study sheds light on bat adaptive immunity and may benefit future vaccine development against bat-borne viruses of high impact on humans.
PLOS Biology, Volume 17; doi:10.1371/journal.pbio.3000437
Abstract:Heart disease is the leading cause of death in the western world. Attaining a mechanistic understanding of human heart development and homeostasis and the molecular basis of associated disease states relies on the use of animal models. Here, we present the cardiac proteomes of 4 model vertebrates with dual circulatory systems: the pig (Sus scrofa), the mouse (Mus musculus), and 2 frogs (Xenopus laevis and Xenopus tropicalis). Determination of which proteins and protein pathways are conserved and which have diverged within these species will aid in our ability to choose the appropriate models for determining protein function and to model human disease. We uncover mammalian- and amphibian-specific, as well as species-specific, enriched proteins and protein pathways. Among these, we find and validate an enrichment in cell-cycle–associated proteins within Xenopus laevis. To further investigate functional units within cardiac proteomes, we develop a computational approach to profile the abundance of protein complexes across species. Finally, we demonstrate the utility of these data sets for predicting appropriate model systems for studying given cardiac conditions by testing the role of Kielin/chordin-like protein (Kcp), a protein found as enriched in frog hearts compared to mammals. We establish that germ-line mutations in Kcp in Xenopus lead to valve defects and, ultimately, cardiac failure and death. Thus, integrating these findings with data on proteins responsible for cardiac disease should lead to the development of refined, species-specific models for protein function and disease states.
PLOS Biology, Volume 17; doi:10.1371/journal.pbio.3000393
Abstract:The ribosome moves between distinct structural states and is organized into multiple functional domains. Here, we examined hundreds of occurrences of pairwise through-space communication between nucleotides in the ribosome small subunit RNA using RNA interaction groups analyzed by mutational profiling (RING-MaP) single-molecule correlated chemical probing in bacterial cells. RING-MaP revealed four structural communities in the small subunit RNA, each distinct from the organization defined by the RNA secondary structure. The head domain contains 2 structural communities: the outer-head contains the pivot for head swiveling, and an inner-head community is structurally integrated with helix 44 and spans the entire ribosome intersubunit interface. In-cell binding by the antibiotic spectinomycin (Spc) barely perturbs its local binding pocket as revealed by the per-nucleotide chemical probing signal. In contrast, Spc binding overstabilizes long-range RNA–RNA contacts that extend 95 Å across the ribosome that connect the pivot for head swiveling with the axis of intersubunit rotation. The two major motions of the small subunit—head swiveling and intersubunit rotation—are thus coordinated via long-range RNA structural communication, which is specifically modulated by Spc. Single-molecule correlated chemical probing reveals trans-domain structural communication and rationalizes the profound functional effects of binding by a low–molecular-mass antibiotic to the megadalton ribosome.
PLOS Biology, Volume 17; doi:10.1371/journal.pbio.3000446
Abstract:Toxoplasma gondii is a remarkably successful protozoan parasite that infects a third of the human population, along with most mammals and birds. However, the sexual portion of the parasite’s life cycle is narrowly limited to cats. How parasites distinguish between hosts has long been a mystery. A new study reveals that Toxoplasma identifies cats based on a single fatty acid, linoleic acid. Experimental manipulation of fatty acid metabolism by drug treatment turns a mouse into a cat in the “eye” of the parasite. This new model enables genetic crosses of an important human pathogen without the use of companion animals and opens the door to future discovery.
PLOS Biology, Volume 17; doi:10.1371/journal.pbio.3000419
Abstract:Parvalbumin (PV)-positive interneurons modulate cortical activity through highly specialized connectivity patterns onto excitatory pyramidal neurons (PNs) and other inhibitory cells. PV cells are autoconnected through powerful autapses, but the contribution of this form of fast disinhibition to cortical function is unknown. We found that autaptic transmission represents the most powerful inhibitory input of PV cells in neocortical layer V. Autaptic strength was greater than synaptic strength onto PNs as a result of a larger quantal size, whereas autaptic and heterosynaptic PV-PV synapses differed in the number of release sites. Overall, single-axon autaptic transmission contributed to approximately 40% of the global inhibition (mostly perisomatic) that PV interneurons received. The strength of autaptic transmission modulated the coupling of PV-cell firing with optogenetically induced γ-oscillations, preventing high-frequency bursts of spikes. Autaptic self-inhibition represents an exceptionally large and fast disinhibitory mechanism, favoring synchronization of PV-cell firing during cognitive-relevant cortical network activity.
PLOS Biology, Volume 17; doi:10.1371/journal.pbio.3000113
Abstract:The initial host response to fungal pathogen invasion is critical to infection establishment and outcome. However, the diversity of leukocyte–pathogen interactions is only recently being appreciated. We describe a new form of interleukocyte conidial exchange called “shuttling.” In Talaromyces marneffei and Aspergillus fumigatus zebrafish in vivo infections, live imaging demonstrated conidia initially phagocytosed by neutrophils were transferred to macrophages. Shuttling is unidirectional, not a chance event, and involves alterations of phagocyte mobility, intercellular tethering, and phagosome transfer. Shuttling kinetics were fungal-species–specific, implicating a fungal determinant. β-glucan serves as a fungal-derived signal sufficient for shuttling. Murine phagocytes also shuttled in vitro. The impact of shuttling for microbiological outcomes of in vivo infections is difficult to specifically assess experimentally, but for these two pathogens, shuttling augments initial conidial redistribution away from fungicidal neutrophils into the favorable macrophage intracellular niche. Shuttling is a frequent host–pathogen interaction contributing to fungal infection establishment patterns.
PLOS Biology, Volume 17; doi:10.1371/journal.pbio.3000087
Abstract:Kabuki Syndrome patients have a spectrum of congenital disorders, including congenital heart defects, the primary determinant of mortality. Seventy percent of Kabuki Syndrome patients have mutations in the histone methyl-transferase KMT2D. However, the underlying mechanisms that drive these congenital disorders are unknown. Here, we generated and characterized zebrafish kmt2d null mutants that recapitulate the cardinal phenotypic features of Kabuki Syndrome, including microcephaly, palate defects, abnormal ear development, and cardiac defects. The cardiac phenotype consists of a previously unknown vasculogenesis defect that affects endocardium patterning and, consequently, heart ventricle lumen formation. Additionally, zebrafish kmt2d null mutants have angiogenesis defects depicted by abnormal aortic arch development, hyperactive ectopic blood vessel sprouting, and aberrant patterning of the brain vascular plexus. We demonstrate that zebrafish kmt2d null mutants have robust Notch signaling hyperactivation in endocardial and endothelial cells, including increased protein levels of the Notch transcription factor Rbpj. Our zebrafish Kabuki Syndrome model reveals a regulatory link between the Notch pathway and Kmt2d during endothelium and endocardium patterning and shows that pharmacological inhibition of Notch signaling rebalances Rbpj protein levels and rescues the cardiovascular phenotype by enhancing endothelial and endocardial cell proliferation and stabilizing endocardial patterning. Taken together, these findings demonstrate that Kmt2d regulates vasculogenesis and angiogenesis, provide evidence for interactions between Kmt2d and Notch signaling in Kabuki Syndrome, and suggest future directions for clinical research.
PLOS Biology, Volume 17; doi:10.1371/journal.pbio.3000378
Abstract:During terminal differentiation, most cells exit the cell cycle and enter into a prolonged or permanent G0 in which they are refractory to mitogenic signals. Entry into G0 is usually initiated through the repression of cell cycle gene expression by formation of a transcriptional repressor complex called dimerization partner (DP), retinoblastoma (RB)-like, E2F and MuvB (DREAM). However, when DREAM repressive function is compromised during terminal differentiation, additional unknown mechanisms act to stably repress cycling and ensure robust cell cycle exit. Here, we provide evidence that developmentally programmed, temporal changes in chromatin accessibility at a small subset of critical cell cycle genes act to enforce cell cycle exit during terminal differentiation in the Drosophila melanogaster wing. We show that during terminal differentiation, chromatin closes at a set of pupal wing enhancers for the key rate-limiting cell cycle regulators Cyclin E (cycE), E2F transcription factor 1 (e2f1), and string (stg). This closing coincides with wing cells entering a robust postmitotic state that is strongly refractory to cell cycle reactivation, and the regions that close contain known binding sites for effectors of mitogenic signaling pathways such as Yorkie and Notch. When cell cycle exit is genetically disrupted, chromatin accessibility at cell cycle genes remains unaffected, and the closing of distal enhancers at cycE, e2f1, and stg proceeds independent of the cell cycling status. Instead, disruption of cell cycle exit leads to changes in accessibility and expression of a subset of hormone-induced transcription factors involved in the progression of terminal differentiation. Our results uncover a mechanism that acts as a cell cycle–independent timer to limit the response to mitogenic signaling and aberrant cycling in terminally differentiating tissues. In addition, we provide a new molecular description of the cross talk between cell cycle exit and terminal differentiation during metamorphosis.
PLOS Biology, Volume 17; doi:10.1371/journal.pbio.3000414
Abstract:Bardet-Biedl syndrome (BBS), a ciliopathy, is a rare genetic condition characterised by retinal degeneration, obesity, kidney failure, and cognitive impairment. In spite of progress made in our general understanding of BBS aetiology, the molecular and cellular mechanisms underlying cognitive impairment in BBS remain elusive. Here, we report that the loss of BBS proteins causes synaptic dysfunction in principal neurons, providing a possible explanation for the cognitive impairment phenotype observed in BBS patients. Using synaptosomal proteomics and immunocytochemistry, we demonstrate the presence of Bbs proteins in the postsynaptic density (PSD) of hippocampal neurons. Loss of Bbs results in a significant reduction of dendritic spines in principal neurons of Bbs mouse models. Furthermore, we show that spine deficiency correlates with events that destabilise spine architecture, such as impaired spine membrane receptor signalling, known to be involved in the maintenance of dendritic spines. Our findings suggest a role for BBS proteins in dendritic spine homeostasis that may be linked to the cognitive phenotype observed in BBS.
PLOS Biology, Volume 17; doi:10.1371/journal.pbio.3000356
Abstract:Natural microbial communities perform many functions that are crucial for human well-being. Yet we have very little control over them, and we do not know how to optimize their functioning. One idea is to breed microbial communities as we breed dogs: by comparing a set of microbiomes and allowing the best-performing ones to generate new communities, and so on. Although this idea seems simple, designing such a selection experiment brings with it many decisions with surprising outcomes. Xie and colleagues developed a computational model that reveals this complexity and shows how different experimental design decisions can impact the success of such an experiment.