ClanTox: a classifier of short animal toxins

Toxins are detected in sporadic species along the evolutionary tree of the animal kingdom. Venomous animals include scorpions, snakes, bees, wasps, frogs and numerous animals living in the sea such as the stonefish, snail, jellyfish, hydra and more. Interestingly, proteins that share a common scaffold with animal toxins also exist in non-venomous species. However, due to their short length and primary sequence diversity, these, toxin-like proteins remain undetected by classical search engines and genome annotation tools. We construct a toxin classification machine and web server called ClanTox (Classifier of Animal Toxins) that is based on the extraction of sequence-driven features from the primary protein sequence followed by the application of a classification system trained on known animal toxins. For a given input list of sequences, from venomous or non-venomous settings, the ClanTox system predicts whether each sequence is toxin-like. ClanTox provides a ranked list of positively predicted candidates according to statistical confidence. For each protein, additional information is presented including the presence of a signal peptide, the number of cysteine residues and the associated functional annotations. ClanTox is a discovery-prediction tool for a relatively overlooked niche of toxin-like cell modulators, many of which are therapeutic agent candidates. The ClanTox web server is freely accessible at http://www.clantox.cs.huji.ac.il

A predictor for toxin-like proteins exposes cell modulator candidates within viral genomes

Motivation: Animal toxins operate by binding to receptors and ion channels. These proteins are short and vary in sequence, structure and function. Sporadic discoveries have also revealed endogenous toxin-like proteins in non-venomous organisms. Viral proteins are the largest group of quickly evolving proteomes. We tested the hypothesis that toxin-like proteins exist in viruses and that they act to modulate functions of their hosts

A roadmap for gene functional characterisation in wheat

To adapt to the challenges of climate change and the growing world population, it is vital to increase global crop production. Understanding the function of genes within staple crops will accelerate crop improvement by allowing targeted breeding approaches. Despite the importance of wheat, which provides 20 % of the calories consumed by humankind, a lack of genomic information and resources has hindered the functional characterisation of genes in this species. The recent release of a high-quality reference sequence for wheat underpins a suite of genetic and genomic resources that support basic research and breeding. These include accurate gene model annotations, gene expression atlases and gene networks that provide background information about putative gene function. In parallel, sequenced mutation populations, improved transformation protocols and structured natural populations provide rapid methods to study gene function directly. We highlight a case study exemplifying how to integrate these resources to study gene function in wheat and thereby accelerate improvement in this important crop. We hope that this review provides a helpful guide for plant scientists, especially those expanding into wheat research for the first time, to capitalise on the discoveries made in Arabidopsis and other plants. This will accelerate the improvement of wheat, a complex polyploid crop, of vital importance for food and nutrition security

Gramene 2018: unifying comparative genomics and pathway resources for plant research

Gramene (http://www.gramene.org) is a knowledgebase for comparative functional analysis in major crops and model plant species. The current release, #54, includes over 1.7 million genes from 44 reference genomes, most of which were organized into 62,367 gene families through orthologous and paralogous gene classification, whole-genome alignments, and synteny. Additional gene annotations include ontology-based protein structure and function; genetic, epigenetic, and phenotypic diversity; and pathway associations. Gramene's Plant Reactome provides a knowledgebase of cellular-level plant pathway networks. Specifically, it uses curated rice reference pathways to derive pathway projections for an additional 66 species based on gene orthology, and facilitates display of gene expression, gene-gene interactions, and user-defined omics data in the context of these pathways. As a community portal, Gramene integrates best-of-class software and infrastructure components including the Ensembl genome browser, Reactome pathway browser, and Expression Atlas widgets, and undergoes periodic data and software upgrades. Via powerful, intuitive search interfaces, users can easily query across various portals and interactively analyze search results by clicking on diverse features such as genomic context, highly augmented gene trees, gene expression anatomograms, associated pathways, and external informatics resources. All data in Gramene are accessible through both visual and programmatic interfaces

Ensembl Genomes 2022: an expanding genome resource for non-vertebrates

Ensembl Genomes (https://www.ensemblgenomes.org) provides access to non-vertebrate genomes and analysis complementing vertebrate resources developed by the Ensembl project (https://www.ensembl.org). The two resources collectively present genome annotation through a consistent set of interfaces spanning the tree of life presenting genome sequence, annotation, variation, transcriptomic data and comparative analysis. Here we present our largest increase in plant, metazoan and fungal genomes since the project’s inception creating one of the world’s most comprehensive genomic resources and describe our efforts to reduce genome redundancy in our Bacteria portal. We also detail our new efforts in gene annotation, our emerging support for pangenome analysis and efforts to accelerate data dissemination through the Ensembl Rapid Release resource. We also present our new AlphaFold visualisation. Finally, we present details of our future plans including updates on our integration with Ensembl, and how we plan to improve our support for the microbial research community. Software and data are made available without restriction via our website, online tools platform and programmatic interfaces (available under an Apache 2.0 license). Data updates are synchronised with Ensembl’s release cycle

Compartment-Restricted Biotinylation Reveals Novel Features of Prion Protein Metabolism in Vivo

A selective tagging method for detecting minor alternatively-localized populations of a protein is used to study a disease-associated transmembrane form of prion protein. The analysis reveals key features of transmembrane prion protein metabolism and one way this is altered by human disease-causing mutants

The SMC5/6 complex compacts and silences unintegrated HIV-1 DNA and is antagonized by Vpr.

Silencing of nuclear DNA is an essential feature of innate immune responses to invading pathogens. Early in infection, unintegrated lentiviral cDNA accumulates in the nucleus yet remains poorly expressed. In HIV-1-like lentiviruses, the Vpr accessory protein enhances unintegrated viral DNA expression, suggesting Vpr antagonizes cellular restriction. We previously showed how Vpr remodels the host proteome, identifying multiple cellular targets. We now screen these using a targeted CRISPR-Cas9 library and identify SMC5-SMC6 complex localization factor 2 (SLF2) as the Vpr target responsible for silencing unintegrated HIV-1. SLF2 recruits the SMC5/6 complex to unintegrated lentiviruses, and depletion of SLF2, or the SMC5/6 complex, increases viral expression. ATAC-seq demonstrates that Vpr-mediated SLF2 depletion increases chromatin accessibility of unintegrated virus, suggesting that the SMC5/6 complex compacts viral chromatin to silence gene expression. This work implicates the SMC5/6 complex in nuclear immunosurveillance of extrachromosomal DNA and defines its targeting by Vpr as an evolutionarily conserved antagonism

Increased demand for NAD+ relative to ATP drives aerobic glycolysis

Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand that association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD /NADH ratio. This change in NAD /NADH is caused by increased mitochondrial membrane potential that impairs mitochondrial electron transport and NAD regeneration. Uncoupling respiration from ATP synthesis or increasing ATP hydrolysis restores NAD /NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when demand for NAD to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD regeneration by mitochondrial respiration becomes constrained, promoting fermentation, despite available oxygen. This argues that cells engage in aerobic glycolysis when the demand for NAD is in excess of the demand for ATP. + + + + + +