Biology subjects

Brun, C.

Publications and source records attributed to Brun, C..

At least 19 recordsLinked to original sources

bioRxiv2026

BactMentha: a database of annotated bacteria-host protein interactions

Bacterial pathogens ensure their successful dissemination by employing specialized secretion systems to deliver a wide range of virulence proteins that interact with specific host proteins to modulate the response during infection. These interactions are often mediated by host-like elements, like short linear motifs, which can interfere with host interaction interfaces, enabling bacterial secreted proteins to compete and displace native partners of the targeted proteins. Several resources provide access to bacteria-host protein-protein interaction data. However, some are neither fully functional or up to date. Moreover, most of these databases lack virulence protein annotations, thus hampering hypothesis formulation based on protein interaction analyses. In this context, we have developed BactMentha, a unified resource that integrates bacterial-host protein-protein interactions for three organisms (human, mouse, and rat) with virulence protein annotations and bacterial strain clinical relevance information. BactMentha provides easy access to available experimentally identified binding regions of the interaction partners, complemented with putative interaction interfaces based on predicted structure complexes and on the detection of host-like elements on bacterial protein sequences interacting with human proteins. BactMentha currently contains 11 776 unique protein interactions between 2970 bacterial proteins, of which 684 have at least one virulence annotation, and 5088 host proteins. Experimentally identified binding regions are available for 532 bacteria-host interactions, most of which involve human proteins (440 interactions). Predicted interaction interfaces enabled a 3.7-fold increase in known and putative binding regions in the bacteria-human protein interaction data. By providing easy access to functionally annotated and clinically relevant protein interaction data, enriched with experimentally and predicted interaction interfaces, BactMentha can be instrumental in formulating novel hypotheses and speeding up wet lab research on the molecular mechanisms underlying pathogenic bacterial infections.

bioinformatics↗

bioRxiv2026

A quantitative interactome map reveals affinity tailored hijacking of human cellular functions by resident and pathogenic bacteria

Bacteria employ molecular mimicry to hijack host cellular functions for their own benefit. Despite the wealth of data mapping human-bacteria interactions, a comprehensive view of how these networks are fine-tuned remains elusive. In particular, there have been no large-scale screenings measuring human-bacterial protein-protein binding affinities to explore their role in functional and pathological outcomes. Here, we report the largest quantitative interactome to date between the family of human PDZ domains and C-terminal PDZ-binding motifs (PBMs) in effectors from pathogenic and resident gut bacteria. We show that bacteria tailor effector sequences to bind PDZ domains with similar or higher binding affinities than human PBMs to hijack their associated cellular functions. For a subset of the dataset, we validate PDZ-PBM interactions with the corresponding full-length proteins and show that for pathogenic E. coli effector NleA, its C-terminal PBM is necessary for interactions with proteins involved in intracellular transport and membrane organization, probably impacting the host glycocalyx to favor infection. Finally, we show that motifs overlapping with effector PBMs target interaction modules other than PDZ domains, adding an additional layer of complexity to the host-microbe molecular dialogue.

systems biology↗

bioRxiv2026

Host recovery after skin barrier disruption is individual-specific and associated with microbial functions

The human skin is repeatedly exposed to mechanical and environmental stress, particularly in common skin diseases such as eczema, and yet the determinants of recovery remain poorly understood. Using longitudinal, multimodal profiling of skin physiology, structure (Raman spectroscopy), and microbial communities (shotgun metagenomics), we investigated in a human cohort (n=36 subjects, x2 sites, x6 timepoints) how host-microbe interactions could jointly shape recovery. Despite baseline variability in physiological parameters, we established that our protocol enables a defined disruption of the stratum corneum. While recovery trajectories for host attributes were notably consistent across age groups and body sites, individual-specific differences in recovery timelines were observed. To assess the role of the skin microbiome, several key time-dependent changes in microbial species were identified including enrichment of select Cutibacterium and Staphylococcus species and depletion of Corynebacterium and Malassezia species. Clustering of microbiome stability profiles across subjects and sites identified 6 distinct groups which associate with varying host-recovery patterns and microbial functions. Finally, joint hazards modelling of recovery timing revealed significant contributions from microbial taxa, functions and stability groups, highlighting the under-appreciated role of host-microbial interactions in response to skin stress and in the recovery process.

genomics↗

bioRxiv2025

Drosophila melanogaster miPEP8 regulates cell size through its interaction with ref(2)P/p62

MiPEPs are microproteins encoded by primary transcripts of microRNAs (pri-miRNAs). Initially identified in plants, we recently characterized a miPEP in Drosophila melanogaster, named miPEP8, which is involved in the regulation of wing size. However, mechanisms at play are unknown. In the present study, we take advantage of the drosophila cell line Schneider 2 (S2) to further investigate miPEP8 function at the molecular level. Overexpressing miPEP8 in S2 cells induced a reduction of cell size as well as an increase of the proportion of cells in the G1 phase of the cell cycle and an increase of the autophagic flux. A proteomics analysis revealed that miPEP8 overexpression in S2 cells induces the upregulation of several proteins including the autophagosome cargo protein ref(2)P (the orthologue of the human p62/Sequestosome 1 protein). The interactome of miPEP8 was generated and revealed interactions between this miPEP8 and the mTORC1/autophagy pathway. Bioinformatics analysis identified a short linear motif (SLiM) on miPEP8 sequence. Mutation of this SLiM prevented the interaction between ref(2)P/p62 and miPEP8. Mutation of the SLiM also reverted the smaller cell size phenotype observed when overexpressing miPEP8 in S2 cells. Finally, the cell size phenotype was reversed when cells were treated with RNA interference targeting ref(2)P/p62, suggesting that this protein plays a role in regulating the cell size in Drosophila.

biochemistry↗

bioRxiv2025

LAM/TREM2+ macrophages release extracellular vesicles and extracellular lipid droplets which modulate the phenotype of recipient macrophages and homeostasis of skeletal muscle cells

The polarization of tissue-resident macrophages is influenced by a variety of signals from the immune system and the local tissue environment, including nutrition. Although it is known that the quality and quantity of ingested lipids have a significant effect on the lipid composition of extracellular vesicles and their fate, it is unknown how the nutritional environment modifies the release and the function of macrophage-derived EVs. In this study, we used a combination of palmitate and oleate (1:2, FFA) to generate lipid-associated TREM2-expressing macrophages (LAM/TREM2+) in vitro. Using various electron microscopy techniques (TEM, SEM, CryoEM) and fluorophores, we found that FFA overload not only induces lipid storage in LAM/TREM2+ macrophages, but also alters their morphology and reduces the diversity and the number of the lipid-derived structures they release. In addition, LAM/TREM2+ macrophages accumulated lipid droplets (LDs) below the plasma membrane and we discovered for the first time that they export and disseminate full LDs into their environment, in addition to extracellular vesicles, by using a cellular pathway associated to CD81. The use of 14C-palmitate confirmed the presence of 14C-triacylglycerols in the large extracellular vesicle pellet. LAM/TREM2+ macrophage-derived EVs induced TREM2 and Il-10 expression in recipient M0 macrophages. These data provide potential insights into how dietary factors and metabolic perturbations can shape the functions of macrophage-derived EVs in the context of metabolic diseases such as diabetes and obesity. In addition, LAM/TREM2+ macrophage-derived EVs modulated insulin-sensitivity, mitochondrial oxidative capacity, lipid profiles and the expressions of genes encoding extracellular matrix components in recipient skeletal muscle cells. Although previously postulated but never demonstrated, these data also highlight the LAM/TREM2+ macrophage-derived EVs as important players in SkM tissue renewal and metabolic homeostasis.

cell biology↗

bioRxiv2024

InteractORF, predictions of human sORF functions from an interactome study

Short open reading frames (sORFs) are widespread yet often poorly annotated, and an increasing number are known to encode functional sORF-encoded peptides (sPEPs, or microproteins). Here, we use a system approach to determine the functions of sPEPs in three tissues: monocytes, skeletal muscle and brain. We first predicted interactions between sPEPs and canonical proteins and characterized their interaction interfaces. sPEPs preferentially target specific canonical partners rather than interacting promiscuously, and two functional groups emerge from their interaction features. A small subset (~2%) exhibits canonical protein-like features, with structured domains interacting with diverse proteins involved in tissue-specific functions. In contrast, most sPEPs contain short linear motifs with extensive phosphorylation potential, suggesting they may be involved in signaling. We then constructed the first sPEP-containing interactome networks and infer sPEP functions from network topology. Most sPEPs appear to act as regulatory elements modulating diverse cellular processes rather than acting directly as functional components. Knowledge-based validations using characterized sPEPs, show that our framework can capture context-specific functions beyond current annotations. Together with their limited evolutionary constraint, the pervasive regulatory roles of sPEPs suggest that they constitute a reservoir of functional novelty and an evolutionarily flexible layer of cellular regulation.

bioinformatics↗

bioRxiv2024

Setting Climate Targets: The Case of Higher Education and Research

The carbon footprint and low-carbon strategies of higher education and research organizations have been the subject of scientific articles and reports. However, these provide few details on the reduction targets themselves, leaving the question of how should higher education and research organizations define and construct their climate targets and trajectories unanswered. The present paper fills this gap. We first review and analyze the documents describing the climate strategies of 53 higher education and research organizations coming from 11 countries, based on their detailed GreenHouse Gas emissions (GHGs) reporting. The selected reports include at least one target re-duction for at least one target year. Then, on the basis of this analysis we propose guidelines to encourage and help higher education and research organizations set rele-vant climate targets.

scientific communication and education↗

bioRxiv2024

Fundamental principles of chromosome organization for meiotic recombination

In meiotic cells, chromosomes are organized as chromatin loop arrays anchored to a protein axis. This organization is essential to regulate meiotic recombination, from DNA double-strand break (DSB) formation to their repair 1. In mammals, it is unknown how chromatin loops are organized along the genome and how proteins participating in DSB formation are tethered to the chromosome axes. Here, we identified three categories of axis-associated genomic sites: PRDM9 binding sites, where DSBs form 2, binding sites of the insulator protein CTCF, and H3K4me3-enriched sites. We demonstrated that PRDM9 promotes the recruitment of MEI4 and IHO1, two proteins essential for DSB formation 3,4. In turn, IHO1 anchors DSB sites to the axis components HORMAD1 and SYCP3. We discovered that IHO1, HORMAD1 and SYCP3 are associated at the DSB ends during DSB repair. Our results highlight how interactions of proteins with specific genomic elements shape the meiotic chromosome organization for recombination.

molecular biology↗

bioRxiv2023

A gut meta-interactome map reveals modulation of human immunity by microbiome effectors

The molecular mechanisms by which the gut microbiome influences human health remain largely unknown. Pseudomonadota is the third most abundant phylum in normal gut microbiomes. Several pathogens in this phylum can inject so-called virulence effector proteins into host cells. We report the identification of intact type 3 secretion systems (T3SS) in 5 - 20% of commensal Pseudomonadota in normal human gut microbiomes. To understand their functions, we experimentally generated a high-quality protein-protein meta-interactome map consisting of 1,263 interactions between 289 bacterial effectors and 430 human proteins. Effector targets are enriched for metabolic and immune functions and for genetic variation of microbiome-influenced traits including autoimmune diseases. We demonstrate that effectors modulate NF-{kappa}B signaling, cytokine secretion, and adhesion molecule expression. Finally, effectors are enriched in metagenomes of Crohns disease, but not ulcerative colitis patients pointing toward complex contributions to the etiology of inflammatory bowel diseases. Our results suggest that effector-host protein interactions are an important regulatory layer by which the microbiome impacts human health.

microbiology↗

bioRxiv2023

Setdb1 safeguards genome integrity in muscle stem cells to allow for regenerative myogenesis and inflammation

Modulations in chromatin structure orchestrate gene expression and direct stem cell fate. More specifically, the histone 3 lysine 9 Methyltransferase Setdb1 controls transcriptional repression to regulate pluripotency and self-renewal. While Setdb1 functions have been extensively studied in embryonic stem cells and in cancer cells, less is known on its role in adult stem cells in vivo. Here, we show that Setdb1 expression by adult muscle stem cells (MuSCs) is required for muscle tissue regeneration following acute injury. We find that SETDB1 represses the expression of the endogenous retroviruses (ERVs) family of transposable elements in MuSCs. ERV de-expression in Setdb1-null MuSCs prevents their amplification following exit from quiescence and promotes cell death. Multi-omics profiling further shows that the absence of SETDB1 in MuSCs leads to the activation of the DNA-sensing cGAS-STING pathway, entailing increased cytokine expression. In vivo, conditional disruption of Setdb1 in MuSCs provokes aberrant infiltration of inflammatory cells including the appearance of a pathological macrophage lineage. The ensuing histiocytosis is accompanied by necrosis of the newly formed muscle fibers which, in addition with the progressive loss of MuSCs, completely abolish skeletal muscle tissue repair. In contrast, disruption of Setdb1 gene in another muscle-resident cell type, the fibro-adipogenic progenitors (FAPs), does not impact regenerative inflammation. In conclusion, the control of genome stability by SETDB1 in an adult somatic stem cell is necessary for both its regenerative potential and an adequate inflammation regulating tissue repair.

cell biology↗

bioRxiv2022

mimicINT: a workflow for microbe-host protein interaction inference

BackgroundThe increasing incidence of emerging infectious diseases is posing serious global threats. Therefore, there is a clear need for developing computational methods that can assist and speed up experimental research to better characterize the molecular mechanisms of microbial infections. MethodsIn this context, we developed mimicINT, an open-source computational workflow for large-scale protein-protein interaction inference between microbe and human by detecting putative molecular mimicry elements mediating the interaction with host proteins: short linear motifs (SLiMs) and host-like globular domains. mimicINT exploits these putative elements to infer the interaction with human proteins by using known templates of domain-domain and SLiM-domain interaction templates. mimicINT also provides (i) robust Monte-Carlo simulations to assess the statistical significance of SLiM detection which suffers from false positives, and (ii) an interaction specificity filter to account for differences between motif-binding domains of the same family. We have also made mimicINT available via a web server. ResultsIn two use cases, mimicINT can identify potential interfaces in experimentally detected interaction between pathogenic Escherichia coli type-3 secreted effectors and human proteins and infer biologically relevant interactions between Marburg virus and human proteins. ConclusionsThe mimicINT workflow can be instrumental to better understand the molecular details of microbe-host interactions.

bioinformatics↗

bioRxiv2022

The contrasted impacts of grasshoppers on soil microbial activities in function of ecosystem productivity and herbivore diet

Herbivory can have contrasted impacts on soil microbes and nutrient cycling, which has stimulated the development of conceptual frameworks exploring the links between below- and aboveground processes. The "productivity model" predicts that herbivores stimulate microbial activities and accelerate nutrient mineralization in productive ecosystems, while they have an opposite effect in less productive ecosystems. In parallel, the "diet model" predicts that herbivores feeding on conservative plants accelerate nutrient cycling while those feeding on exploitative plants decelerate nutrient cycling, due to changes in litter inputs. Since these two frameworks can lead to conflicting predictions in some cases, experimental evidence combining herbivore diet and plant productivity is required. During two consecutive years, we conducted an experiment controlling the presence of three grasshopper species consuming either grasses, forbs or both in twelve natural and managed alpine grasslands with contrasted productivities. In order to assess the effects of herbivory on soil microbes, we measured their extracellular enzymatic activities, biomass and potential nitrogen mineralization (PNM). Soil and vegetation were also characterized to test how much they modulated the effects of herbivory on microbes. Contrary to the predictions of the diet model, the effects of herbivory on microbial characteristics did not depend on the herbivores diet, but were influenced by primary production, though in a way that differed from the productivity model. The most productive sites were constituted by exploitative plant species which depleted N resources in the soil, and by microbes producing relatively few extracellular enzymes, leading to a lower PNM. Herbivory increased microbial biomass and decreased the production of extracellular enzymes in those sites, possibly through the stimulation of root exudates produced by exploitative species. The least productive sites were characterized by conservative plants, high soil C content, and by microbes having a resource acquisition strategy (more extracellular enzymes, higher PNM). Herbivory decreased microbial biomass and increased the production of extracellular enzymes in those sites. This pattern can be explained by the loss of carbon associated with insect respiration, which increases the resource requirements of microbes and by a lower production of root exudates by conservative species. Therefore, the effects of two years of herbivory on soil microbes were at odds with the productivity model, which focuses instead on longer term effects corresponding to herbivory-induced changes in plant species composition. This highlights the multidimensional feature of the impacts of herbivory on ecosystem functioning, both in space and time.

ecology↗

bioRxiv2022

Social environment and chronological age shape eusocial insect species: the case of the ant workers.

Position within the social group has consequences on individual lifespans in diverse taxa. This is especially obvious in eusocial insects, where workers differ in both the tasks they perform and their aging rates. However, in eusocial wasps, bees and ants, the performed task usually depends strongly on age. As such, untangling the effects of social role and age on worker physiology is a key step towards understanding the coevolution of sociality and aging. We performed an experimental protocol that allowed a separate analysis of these two factors using four groups of black garden ant (Lasius niger) workers: young foragers, old foragers, young nest workers, and old nest workers. We highlighted age-related differences in the proteome and metabolome of workers that were primarily related to worker subcaste and only secondarily to age. The relative abundance of proteins and metabolites suggests an improved xenobiotic detoxification, and a fuel metabolism based more on lipid use than carbohydrate use in young ants, regardless of their social role. Regardless of age, proteins related to the digestive function were more abundant in nest workers than in foragers. Old foragers were mostly characterized by weak abundances of molecules with an antibiotic activity or involved in chemical communication. Finally, our results suggest that even in tiny species, extended lifespan may require to mitigate cancer risks. This is consistent with results found in eusocial rodents and thus opens up the discussion of shared mechanisms among distant taxa and the influence of sociality on life history traits such as longevity.

physiology↗

bioRxiv2022

In depth exploration of the alternative proteome of Drosophila melanogaster

Recent studies have shown that hundreds of small proteins were occulted when protein coding genes were annotated. These proteins, called alternative proteins, have failed to be annotated notably due to the short length of their open reading frame (less than 100 codons) or the enforced rule establishing that messenger RNAs (mRNAs) are monocystronic. Several alternative proteins were shown to be biologically active molecules and seem to be involved in a wide range of biological functions. However, genome wide exploration of the alternative proteome is still limited to a few species. In the present article we describe a deep peptidomics workflow which enabled the identification of 401 alternative proteins in Drosophila melanogaster. Subcellular localization, protein domains and short linear motifs were predicted for 235 of the alternative proteins identified and point towards specific functions of these small proteins. Several alternative proteins had approximated abundances higher than their canonical counterparts, suggesting that these alternative proteins are actually the main products of their corresponding genes. Finally, we observed fourteen alternative proteins with developmentally regulated expression patterns and ten induced upon heat shock treatment of embryos, demonstrating stage or stress specific production of alternative proteins.

biochemistry↗

bioRxiv2021

Epi-MEIF, a flexible and efficient method for detection of high order epistatic interactions from complex phenotypic traits

Understanding the relationship between genetic variations and variations in complex and quantitative phenotypes remains an ongoing challenge. While Genome-wide association studies (GWAS) have become a vital tool for identifying single-locus associations, we lack methods for identifying epistatic interactions. In this article, we propose a novel method for high-order epistasis detection using mixed effect conditional inference forest (epiMEIF). The epiMEIF model is fitted on a group of potential causal SNPs and the tree structure in the forest facilitates the identification of n-way interactions between the SNPs. Additional testing strategies further improve the robustness of the method. We demonstrate its ability to detect true n-way interactions via extensive simulations in both cross-sectional and longitudinal synthetic datasets. This is further illustrated in an application to reveal epistatic interactions from natural variations of cardiac traits in flies (Drosophila). Overall, the method provides a generalized way to identify high order interactions from any GWAS data, thereby greatly improving the detection of the genetic architecture of complex phenotypes.

genetics↗

bioRxiv2021

Molecular liver fingerprint reflects the seasonal physiology of the grey mouse lemur (Microcebus murinus) during winter

Grey mouse lemurs (Microcebus murinus) are a primate species exhibiting strong physiological seasonality in response to environmental energetic constraint. They notably store large amounts of lipids during early winter (EW), which are thereafter mobilized during late winter (LW), when food availability is low. In addition, they develop glucose intolerance in LW only. To decipher how the hepatic mechanisms may support such metabolic flexibility, we analyzed the liver proteome of adult captive male mouse lemurs, which seasonal regulations of metabolism and reproduction are comparable to their wild counterparts, during the phases of either constitution or use of fat reserves. We highlight profound changes that reflect fat accretion in EW at the whole-body level, however, without triggering an ectopic storage of fat in the liver. Moreover, molecular regulations would be in line with the lowering of liver glucose utilization in LW, and thus with reduced tolerance to glucose. However, no major regulation was seen in insulin signaling/resistance pathways, which suggests that glucose intolerance does not reach a pathological stage. Finally, fat mobilization in LW appeared possibly linked to reactivation of the reproductive system and enhanced liver detoxification may reflect an anticipation to return to summer levels of food intake. Altogether, these results show that the physiology of mouse lemurs during winter relies on solid molecular foundations in liver processes to adapt fuel partitioning while avoiding reaching a pathological state despite large lipid fluxes. This work emphasizes how the mouse lemur is of primary interest for identifying molecular mechanisms relevant to biomedical field.

molecular biology↗

bioRxiv2021

TOPOVIBL-REC114 interaction regulates meiotic DNA double-strand breaks

Meiosis requires the formation of programmed DNA double strand breaks (DSBs), essential for fertility and for generating genetic diversity. DSBs are induced by the catalytic activity of the TOPOVIL complex formed by SPO11 and TOPOVIBL. To ensure genomic integrity, DNA cleavage activity is tightly regulated, and several accessory factors (REC114, MEI4, IHO1, and MEI1) are needed for DSB formation in mice. How and when these proteins act is not understood. Here, we show that REC114 is a direct partner of TOPOVIBL, and identified their conserved interacting domains by structural analysis. We then analysed the role of this interaction by monitoring meiotic DSBs in female and male mice carrying point mutations in TOPOVIBL that decrease or disrupt its binding to REC114. In these mutants, DSB activity was strongly reduced genome-wide in oocytes, and only in sub-telomeric regions in spermatocytes. In addition, in mutant spermatocytes, DSB activity was delayed in autosomes. These results provide evidence that REC114 is a key member of the TOPOVIL catalytic complex, and that the REC114/TOPOVIBL interaction ensures the efficiency and timing of DSB activity.

molecular biology↗

bioRxiv2021

Genetic architecture of natural variations of cardiac performance in flies

Deciphering the genetic architecture of human cardiac disorders is of fundamental importance but their underlying complexity is a major hurdle. We investigated the natural variation of cardiac performance in the sequenced inbred lines of the Drosophila Genetic Reference Panel (DGRP). Genome Wide Associations Studies (GWAS) identified genetic networks associated with natural variation of cardiac traits which were used to gain insights as to the molecular and cellular processes affected. Non-coding variants that we identified were used to map potential regulatory non-coding regions, which in turn were employed to predict Transcription Factors (TFs) binding sites. Cognate TFs, many of which themselves bear polymorphisms associated with variations of cardiac performance, were also validated by heart specific knockdown. Additionally, we showed that the natural variations associated with variability in cardiac performance affect a set of genes overlapping those associated with average traits but through different variants in the same genes. Furthermore, we showed that phenotypic variability was also associated with natural variation of gene regulatory networks. More importantly, we documented correlations between genes associated with cardiac phenotypes in both flies and humans, which supports a conserved genetic architecture regulating adult cardiac function from arthropods to mammals. Specifically, roles for PAX9 and EGR2 in the regulation of the cardiac rhythm were established in both models, illustrating that the characteristics of natural variations in cardiac function identified in Drosophila can accelerate discovery in humans.

genetics↗