The aim of the UniProt Knowledgebase is to provide users with a comprehensive, high-quality and freely accessible set of protein sequences annotated with functional information. In this article, we describe significant updates that we have made over the last two years to the resource. The number of sequences in UniProtKB has risen to approximately 190 million, despite continued work to reduce sequence redundancy at the proteome level. We have adopted new methods of assessing proteome completeness and quality. We continue to extract detailed annotations from the literature to add to reviewed entries and supplement these in unreviewed entries with annotations provided by automated systems such as the newly implemented Association-Rule-Based Annotator (ARBA). We have developed a credit-based publication submission interface to allow the community to contribute publications and annotations to UniProt entries. We describe how UniProtKB responded to the COVID-19 pandemic through expert curation of relevant entries that were rapidly made available to the research community through a dedicated portal. UniProt resources are available under a CC-BY (4.0) license via the web at https://www.uniprot.org/.

The aim of the UniProt Knowledgebase is to provide users with a comprehensive, high-quality and freely accessible set of protein sequences annotated with functional information. In this publication we describe enhancements made to our data processing pipeline and to our website to adapt to an ever-increasing information content. The number of sequences in UniProtKB has risen to over 227 million and we are working towards including a reference proteome for each taxonomic group. We continue to extract detailed annotations from the literature to update or create reviewed entries, while unreviewed entries are supplemented with annotations provided by automated systems using a variety of machine-learning techniques. In addition, the scientific community continues their contributions of publications and annotations to UniProt entries of their interest. Finally, we describe our new website (https://www.uniprot.org/), designed to enhance our users’ experience and make our data easily accessible to the research community. This interface includes access to AlphaFold structures for more than 85% of all entries as well as improved visualisations for subcellular localisation of proteins.

Synthetic chemicals currently used in a variety of industrial and agricultural applications are leading to widespread contamination of the environment. Even though the intended uses of pesticides, plasticizers, antimicrobials, and flame retardants are beneficial, effects on human health are a global concern. These so-called endocrine-disrupting chemicals (EDCs) can disrupt hormonal balance and result in developmental and reproductive abnormalities. New in vitro, in vivo, and epidemiological studies link human EDC exposure with obesity, metabolic syndrome, and type 2 diabetes. Here we review the main chemical compounds that may contribute to metabolic disruption. We then present their demonstrated or suggested mechanisms of action with respect to nuclear receptor signaling. Finally, we discuss the difficulties of fairly assessing the risks linked to EDC exposure, including developmental exposure, problems of high- and low-dose exposure, and the complexity of current chemical environments.

The Gene Ontology (GO) knowledgebase (http://geneontology.org) is a comprehensive resource concerning the functions of genes and gene products (proteins and non-coding RNAs). GO annotations cover genes from organisms across the tree of life as well as viruses, though most gene function knowledge currently derives from experiments carried out in a relatively small number of model organisms. Here, we provide an updated overview of the GO knowledgebase, as well as the efforts of the broad, international consortium of scientists that develops, maintains and updates the GO knowledgebase. The GO knowledgebase consists of three components: 1) the Gene Ontology – a computational knowledge structure describing functional characteristics of genes; 2) GO annotations – evidence-supported statements asserting that a specific gene product has a particular functional characteristic; and 3) GO Causal Activity Models (GO-CAMs) – mechanistic models of molecular “pathways” (GO biological processes) created by linking multiple GO annotations using defined relations. Each of these components is continually expanded, revised and updated in response to newly published discoveries, and receives extensive QA checks, reviews and user feedback. For each of these components, we provide a description of the current contents, recent developments to keep the knowledgebase up to date with new discoveries, as well as guidance on how users can best make use of the data we provide. We conclude with future directions for the project.

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BackgroundThe modulation of energetic homeostasis by pollutants has recently emerged as a potential contributor to the onset of metabolic disorders. Diethylhexyl phthalate (DEHP) is a widely used industrial plasticizer to which humans are widely exposed. Phthalates can activate the three peroxisome proliferator–activated receptor (PPAR) isotypes on cellular models and induce peroxisome proliferation in rodents.ObjectivesIn this study, we aimed to evaluate the systemic and metabolic consequences of DEHP exposure that have remained so far unexplored and to characterize the underlying molecular mechanisms of action.MethodsAs a proof of concept and mechanism, genetically engineered mouse models of PPARs were exposed to high doses of DEHP, followed by metabolic and molecular analyses.ResultsDEHP-treated mice were protected from diet-induced obesity via PPARα-dependent activation of hepatic fatty acid catabolism, whereas the activity of neither PPARβ nor PPARγ was affected. However, the lean phenotype observed in response to DEHP in wild-type mice was surprisingly abolished in PPARα-humanized mice. These species differences are associated with a different pattern of coregulator recruitment.ConclusionThese results demonstrate that DEHP exerts species-specific metabolic actions that rely to a large extent on PPARα signaling and highlight the metabolic importance of the species-specific activation of PPARα by xenobiotic compounds.

The concept of endocrine disruption emerged over a decade ago with the observation that several natural or industrial compounds can interfere with estrogen and androgen signaling, and thereby affect both male and female reproductive functions. Since then, many endocrine-disrupting chemicals (EDCs) have been identified and the concept has been broadened to receptors regulating other aspects of endocrine pathways. In that context, interference of EDCs with receptors regulating metabolism has been proposed as a factor that could contribute to metabolic diseases such as obesity and diabetes. We review recent studies showing that several pollutants, including phthalates and organotins, interfere with PPAR (peroxisome proliferator-activated receptors) nuclear receptors and may thereby affect metabolic homeostasis. Particular emphasis is given on the mechanisms of action of these compounds. However, unlike what has been suspected, we provide evidence from mouse models suggesting that in utero exposure to the phthalate ester di-ethyl-hexyl-phthalate most likely does not predispose to obesity. Collectively, these studies define a subclass of EDCs that perturb metabolic signaling and that we propose to define as metabolic disruptors.

MAPK phosphatase-1 (MKP-1) is a protein phosphatase that plays a crucial role in innate immunity. This phosphatase inactivates ERK1/2, which are involved in two opposite functional activities of the macrophage, namely proliferation and activation. Here we found that although macrophage proliferation and activation induce MKP-1 with different kinetics, gene expression is mediated by the proximal promoter sequences localized between À380 and À180 bp. Mutagenesis experiments of the proximal element determined that CRE/AP-1 is required for LPS-or M-CSF-induced activation of the MKP-1 gene. Moreover, the results from gel shift analysis and chromatin immunoprecipitation indicated that c-Jun and CREB bind to the CRE/AP-1 box. The distinct kinetics shown by M-CSF and LPS correlates with the induction of JNK and c-jun, as well as the requirement for Raf-1. The signal transduction pathways that activate the induction of MKP-1 correlate kinetically with induction by M-CSF and LPS.Key words: Activation . Kinases . Macrophage . Phosphatases . Proliferation IntroductionMacrophages perform critical functions during the immune response. These cells are regulators of homeostasis and play an important role in innate and acquired immunity during infection, tumor growth, and wound healing [1]. In response to needs, tissue macrophages proliferate, further differentiate to more specialized macrophagic populations, or become activated. Macrophages, like many other cells of the immune system, are produced in large excess and most undergo apoptosis [2].In the presence of M-CSF, macrophages differentiate and proliferate. However, the proliferation of these cells is blocked when they are activated by Gram-negative LPS or by . Activation causes many biochemical, morphological and functional modifications. Macrophage response to M-CSF and LPS involves the phosphorylation of the three members of the MAPK family [4].MAPK are critical components of signal transduction pathways activated by a range of stimuli and they mediate a number of physiological and pathological changes in cell function [5,6]. MAPK activation requires phosphorylation on a threonine and tyrosine residue located in the activation loop. This process is reversible even in the continued presence of activating stimuli, thereby indicating that protein phosphatases regulate MAPK [7]. Although MAPK are conserved evolutionary pathways present in eukaryotic cells, the kinetics of activation and their subcellular compartmentalization are cell type-specific, and they orchestrate differential cellular responses. For example, in neuronal cells, sustained MAPK phosphorylation of even days is required for cellular activation or differentiation, while in fibroblasts, phosphorylation of this kinase family is very short. In contrast, to Immunol. 2009. 39: 1902-1913 Cristina Casals-Casas et al. 1902 achieve proliferation, extended activation of MAPK is required in these cells [6,7]. The correct spatio-temporal regulation of MAPK signalling is crucial in determining cellular responses to g...