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Vidal, M.

Publications and source records attributed to Vidal, M..

At least 37 records · Page 2Linked to original sources

Validation of a novel fully immersive Virtual Reality setup with a behavioural study of freely-moving fish

Virtual Reality (VR) enables standardised stimuli to invoke behavioural responses in animals, however, in fish studies VR has been limited to either basic virtual stimulation projected below the bowl for freely-swimming individuals or a simple virtual arena rendered over a large field-of-view for head-restrained individuals. We developed a novel immersive VR setup with real-time rendering of animated 3D scenarios, validated in a proof of concept study on the behaviour of coral reef post-larval fish. Fish use a variety of cues to select a habitat during the recruitment stage, and to recognize conspecifics and predators, but which visual cues are used remains unknown. We measured behavioural responses of groups of five convict surgeonfish (Acanthurus triostegus) to simulations of habitats, static or moving shoals of conspecifics, predators, and non-aggressive heterospecifics. Post-larval fish were consistently attracted to virtual corals and conspecifics presented statically, but repulsed by their predators (bluefin jacks, Caranx melampygus). When simulated shoals passed nearby repeatedly, they were again attracted by conspecifics showing a tendency to follow the shoal, whereas they moved repeatedly to the back of the passing predator shoal. They also discriminated between species of similar sizes: they were attracted more to conspecifics than butterflyfish (Forcipiger longirostris), and repulsed more by predators than parrotfish (Scarus psittacus). The quality of visual simulations was high enough to identify between visual cues - size, body shape, colour pattern - used by post-larval fish in species recognition. Despite a tracking technology limited to fish 2D positions in the aquarium, preventing the real-time updating of the rendered viewpoint, we could show that VR and modern tracking technologies offer new possibilities to investigate fish behaviour through the quantitative analysis of their physical reactions to highly-controlled scenarios.

animal behavior and cognition↗

The reproductive status of the host determines the tolerance and resistance to Mycobacterium marinum infection in Drosophila melanogaster

Both the sex and the reproductive status of the host have a major impact on the regulation of the immune response against infection. Due that Drosophila melanogaster has become a powerful model for study such interactions, we wanted to understand whether the sex or the reproductive status has an impact on the tolerance or resistance of the host to the in the model of systemic Mycobacterium marinum infection. We measured gene expression by RT-qPCR of immune genes, diptericin and drosomycin, as well as host survival and the bacillary load at time of death. We also assessed the impact of metabolic (by expression of upd3 and impl2) and hormonal (by ecR expression) regulation in the protection against infection. Data showed that resistance increased in actively mating males and females, and also in mated females while reducing the tolerance to infection. The data also suggest the Toll and IMD pathways determine tolerance and resistance, respectively, while basal levels of ecR favors the stimulation of the IMD pathway. A time related role has been found for upd3 expression, linked to the increase or decrease in the mycobacterial load at the beginning and at the end of the infection, respectively. Finally, impl2 expression has been related to the increase of resistance only in non-actively mating males. The results obtained allows further interpretation of the results when assessing the differences between sexes and highlights the role of the reproductive status in D. melanogaster to face infections, since our data demonstrated their importance to determine resistance and tolerance against M. marinum infection.

microbiology↗

Next-generation large-scale binary protein interaction network for Drosophila

Generating reference maps of the interactome networks underlying most cellular functions can greatly illuminate genetic studies by providing a protein-centric approach to finding new components of existing pathways, complexes, and processes. Here, we applied state-of-the-art experimental and bioinformatics methods to identify high-confidence binary protein-protein interactions (PPIs) for Drosophila melanogaster. We performed four all-by-all yeast two-hybrid (Y2H) screens of >10,000 Drosophila proteins, resulting in the FlyBi dataset of 8,723 PPIs among 2,939 proteins. As part of this effort, we tested subsets of our data and data from previous PPI datasets using an orthogonal assay, which allowed us to normalize data quality across datasets. Next, we integrated our FlyBi data with previous PPI data, resulting in an expanded, high-confidence binary Drosophila reference interaction network, DroRI, comprising 17,232 interactions among 6,511 proteins. These data are accessible through the Molecular Interaction Search Tool (MIST) and other databases. To assess the utility of the PPI resource, we used novel interactions from the FlyBi dataset to generate an autophagy interaction network that we validated in vivo using two different autophagy-related assays. We found that deformed wings (dwg) encodes a protein that is both a regulator and a target of autophagy. Altogether, the resources generated in this project provide a strong foundation for building high-confidence new hypotheses regarding protein networks and function.

cell biology↗

Genomic adaptation in the CAZyome and specialised metabolism of the plant-associated Streptomyces violaceusniger clade

Streptomycetes are Gram-positive actinobacteria largely represented in the plant root microbiota. The genetic determinants involved in the presence of Streptomyces in the rhizosphere are mostly unknown but can rely on the ability to release phytohormones, degrade plant cell-wall polysaccharides and produce specialised metabolites. Here we sequenced the genome of the rhizospheric and plant defence-stimulating strain Streptomyces sp. AgN23. We found out that it belongs to the soil and plant root dwelling S. violaceusniger clade. The genome annotation of AgN23 revealed the ability of the bacterium to synthesise auxin, a major regulator of plant development, to degrade plant cell wall with a large repertoire of carbohydrate degrading enzymes and to produce antimicrobials (rustmicin, mediomycin, niphimycin, nigericin) and plant bioactive compounds (nigericin, echosides, elaiophylin) through a set of biosynthetic gene clusters. We also found that these genomic features are well-conserved among members of the S. violaceusniger clade. In addition, AgN23 display original events of biosynthetic gene clusters acquisitions and losses which may account for its beneficial effect on plants. Taken together, our work supports the hypothesis that hydrolytic enzymes and specialised metabolites repertoires underpin the interaction of bacteria belonging to the S. violaceusniger clade with plant roots within the rhizosphere. Impact statementStreptomycetes are filamentous Gram-positive bacteria universally found around and within host plant tissues. These actinobacteria have been extensively investigated for their tremendous ability to produce diverse specialised metabolites (e.g., antibiotics). By contrast their impact on host plant physiology is widely neglected. Whether specific lineage of Streptomyces colonise host plant and what are the underlying molecular mechanisms is poorly documented. Here we report a chromosome-scale assembly of AgN23 genome, a Streptomyces sp. strain previously characterised for its ability to activate the plant immune system. This reference sequence enabled us to position AgN23 in the S. violaceusniger clade from which several representatives have been isolated worldwide from the rhizosphere of unrelated plants. Comparative genomic studies suggest that S. violaceusniger spp. produce a prominent CAZyome with expansion of plant cell wall degrading enzymes families and a conserved specialised metabolism acting on host plant physiology and its rhizospheric microbiota. These genomic features may underly S. violaceusniger spp. adaptation to the rhizopsheric niche. Data summaryThe raw reads sequences of AgN23 genome are available at NCBI on the Sequence Read Archive portal for PacBio and MiSeq data (SRR13990229 and SRR14028548 respectively). The Genome assembly is available on the NCBI nucleotide portal under the accession NZ_CP007153.1. This genome sequence was uploaded on the MicroScope platform for genome annotation and analysis (https://mage.genoscope.cns.fr/microscope/home/index.php) [1]. The RNA-seq raw reads are archived in the NCBI Bioproject PRJNA745930. The following eight supplementary tables are included in the online version of this article. Supplementary Information 1: Genomes used in this study. The accession number used from the NCBI portal, name, size, number of contigs as well as the level of completeness of the assembly are indicated. Supplementary Information 2: List of the single copy core genes used by autoMLST to build the phylogenetic tree in Figure 1. O_FIG O_LINKSMALLFIG WIDTH=161 HEIGHT=200 SRC="FIGDIR/small/465742v2_fig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@e15f3org.highwire.dtl.DTLVardef@c34218org.highwire.dtl.DTLVardef@1286956org.highwire.dtl.DTLVardef@1bb5b3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO Multi-locus sequence typing assigned AgN23 to the S. violaceusniger clade. Phylogenetic tree based on the multiple alignment of 85 single-copy homologous genes selected from genomic sequences with AutoMLST. The green node highlights the isolates considered to be from the same species (ANI>95%). The black node highlights the clade formed by isolates with ANI>90% as compared to AgN23. The black squares highlights the eight strains that were used for the BGC conservation study. The green logo indicates plant-isolated strains. Frankia alni ACN14a was used as outgroup, bootstrap=100. C_FIG Supplementary information 3: Annotation of AgN23 full chromosome. For each gene the frame of translation, sequence length and position on the chromosome are indicated. All genes were annotated according to the Microscope platform, see materials and methods. In addition, the expression for each gene is reported in transcripts per million (TPM) based on the the RNA-seq data from three biological replicates. Supplementary Information 4: Genomes having a Mash-based estimated ANI (Average Nucleotide Identity) superior or egal to 80% according to autoMLST. Supplementary Information 5: Prediction of the CAZyme encoding genes using HMMER dbCAN2. The genes are sorted according their CAZy families. For each gene, the begin position on the chromosome, the CAZy category, the annotation, the expression level in transcripts per million (TPM) and the predicted targets of the putative enzymes are described. Supplementary Information 6: Gene identified by antiSMASH in the region containing a biosynthetic gene cluster. Expression levels in transcripts per million (TPM) are indicated for each gene. Annotated central bioynthetic genes are indicated as Y. Those are the ones used for the calculation of mean BGC expression in Table 2. O_TBL View this table: org.highwire.dtl.DTLVardef@1362f24org.highwire.dtl.DTLVardef@50f792org.highwire.dtl.DTLVardef@1ad9681org.highwire.dtl.DTLVardef@1742e96org.highwire.dtl.DTLVardef@9e9b6c_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 2:C_FLOATNO O_TABLECAPTIONantiSMASH annotation of AgN23 chromosomal regions coding for Biosynthetic Gene Clusters. The functional category of each BGCs was determined by antiSMASH. The BGC type, best hit in the MIBiG database as its percentage of similarity to the query are indicated along with the bacterial strain from whom the cluster was described. The expression level of each BGCs was determined by doing the mean of the expression level in Transcripts Per Million (TPM) of the core biosynthetic genes of each BGC from the RNA-seq data (n=3). C_TABLECAPTION C_TBL Supplementary Information 7: Annotation of AgN23 genes putatively involved in biosynthetic pathways for Auxins related phytohomones. Expression levels in transcripts per million (TPM) are indicated for each gene. The genes were detected by blasting reference KEGG sequences for each KEGG ONTOLOGY against AgN23 genes. A cut off of 70% identity and 40% coverage was applied to detect positive hits. These biosynthetic pathways and the KEGG ONTOLOGY are indicated in column F and G. Supplementary Information 8: Inspection of BiG-FAM hits with AgN23 BGCs to identify homologous BGCs found outside the S. violaceusniger clade. BiG-FAM distance higher than 900 were excluded from the analysis. The authors confirm all supporting data, code and protocols have been provided within the article or through supplementary data files.

genomics↗

Protein disulphide isomerase (PDI) is protective against several types of DNA damage, including that induced by amyotrophic lateral sclerosis-associated mutant TDP-43 in neuronal cells/ in vitro models

Protein disulphide isomerase (PDI) is a chaperone that catalyses the formation of thiol-disulphide bonds during protein folding. Whilst up-regulation of PDI is a protective mechanism to regulate protein folding, an increasingly wide range of cellular functions have been ascribed to PDI. Originally identified in the endoplasmic reticulum (ER), PDI has now been detected in many cellular locations, including the nucleus. However, its role in this cellular compartment remains undefined. PDI is implicated in multiple diseases, including amyotrophic lateral sclerosis (ALS), a fatal and rapidly progressing neurodegenerative condition affecting motor neurons. Loss of essential proteins from the nucleus is an important feature of ALS. This includes TAR DNA-binding protein-43 (TDP-43), a DNA/RNA binding protein present in a pathological form in the cytoplasm in almost all (97%) ALS cases, that is also mutated in a proportion of familial cases. PDI is protective against disease-relevant phenotypes associated with dysregulation of protein homeostasis (proteostasis) in ALS. DNA damage is also increasingly linked to ALS, which is induced by pathological forms of TDP-43 by impairment of its normal function in the non-homologous end-joining (NHEJ) mechanism of DNA repair. However, it remains unclear whether PDI is protective against DNA damage in ALS. In this study we demonstrate that PDI was protective against several types of DNA damage, induced by either etoposide, hydrogen peroxide (H2O2), or ALS-associated mutant TDP-43M337V in neuronal cells. This was demonstrated using widely used DNA damage markers, phosphorylated H2AX and 53BP1, which is specific for NHEJ. Moreover, we also show that PDI translocates into the nucleus following DNA damage. Here PDI is recruited directly to sites of DNA damage, implying that it has a direct role in DNA repair. This study therefore identifies a novel role of PDI in the nucleus in preventing DNA damage.

neuroscience↗

A quantitative mapping approach to identify direct interactions within complexomes

Complementary methods are required to fully characterize all protein complexes, or the complexome, of a cell. Affinity purification coupled to mass-spectrometry (AP-MS) can identify the composition of complexes at proteome-scale. However, information on direct contacts between subunits is often lacking. In contrast, solving the 3D structure of protein complexes can provide this information, but structural biology techniques are not yet scalable for systematic, proteome-wide efforts. Here, we optimally combine two orthogonal high-throughput binary interaction assays, LuTHy and N2H, and demonstrate that their quantitative readouts can be used to differentiate direct interactions from indirect associations within multiprotein complexes. We also show that LuTHy allows accurate distance measurements between proteins in live cells and apply these findings to study the impact of the polyglutamine expansion mutation on the structurally unresolved N-terminal domain of Huntingtin. Thus, we present a new framework based on quantitative interaction assays to complement structural biology and AP-MS techniques, which should help to provide first-approximation contact maps of multiprotein complexes at proteome-scale. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/457734v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1cc7cf1org.highwire.dtl.DTLVardef@1eed9borg.highwire.dtl.DTLVardef@8197b2org.highwire.dtl.DTLVardef@e5cb8_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

Plasmodium falciparum and helminth coinfections increase IgE and parasite-specific IgG responses

Coinfection with Plasmodium falciparum and helminths may impact the immune response to these parasites since they induce different immune profiles. We studied the effects of coinfections on the antibody profile in a cohort of 715 Mozambican children and adults using the Luminex technology with a panel of 16 antigens from P. falciparum and 11 antigens from helminths (Ascaris lumbricoides, hookworm, Trichuris trichiura, Strongyloides stercoralis and Schistosoma spp.) and measured antigen-specific IgG and total IgE responses. We compared the antibody profile between groups defined by P. falciparum and helminth previous exposure (based on serology) and/or current infection (determined by microscopy and/or qPCR). In multivariable regression models adjusted by demographic, socioeconomic, water and sanitation variables, individuals exposed/infected with P. falciparum and helminths had significantly higher total IgE and antigen-specific IgG levels, magnitude (sum of all levels) and breadth of response to both types of parasites compared to individuals exposed/infected with only one type of parasite (p[≤] 0.05). There was a positive association between exposure/infection to P. falciparum and exposure/infection to helminths or the number of helminth species, and vice versa (p[≤] 0.001). In addition, children coexposed/coinfected tended (p= 0.062) to have higher P. falciparum parasitemia than those single exposed/infected. Our results suggest that an increase in the antibody responses in coexposed/coinfected individuals may reflect higher exposure and be due to a more permissive immune environment to infection in the host. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/445753v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@a1dc3corg.highwire.dtl.DTLVardef@82128corg.highwire.dtl.DTLVardef@18fcd98org.highwire.dtl.DTLVardef@2d5bb_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

Antibody Conversion rates to SARS-CoV-2 in Saliva from Children Attending Summer Schools in Barcelona, Spain

Surveillance tools to estimate infection rates in young populations are essential to guide recommendations for school reopening and management during viral epidemics. Ideally, field-deployable non-invasive, sensitive techniques are required to detect low viral load exposures among asymptomatic children. We determined SARS-CoV-2 antibody conversion by high-throughput Luminex assays in saliva samples collected weekly in 1,509 children and 396 adults in 22 Summer schools and 2 pre-schools in 27 venues in Barcelona, Spain, from June 29th to July 31st 2020, between the first and second COVID-19 pandemic waves. Saliva antibody conversion defined as [≥]4-fold increase in IgM, IgA and/or IgG levels to SARS-CoV-2 antigens between two visits over a 5-week period was 3.22% (49/1518), or 2.36% if accounting for potentially cross-reactive antibodies, six times higher than the cumulative infection rate (0.53%) by weekly saliva RT-PCR screening. IgG conversion was higher in adults (2.94%, 11/374) than children (1.31%, 15/1144) (p=0.035), IgG and IgA levels moderately increased with age, and antibodies were higher in females. Most antibody converters increased both IgG and IgA antibodies but some augmented either IgG or IgA, with a faster decay over time for IgA than IgG. Nucleocapsid rather than spike was the main antigen target. Anti-spike antibodies were significantly higher in individuals not reporting symptoms than symptomatic individuals, suggesting a protective role against COVID-19. To conclude, saliva antibody profiling including three isotypes and multiplexing antigens is a useful and more user-friendly tool for screening pediatric populations to determine SARS-CoV-2 exposure and guide public health policies during pandemics.

immunology↗

Binary Interactome Models of Inner- Versus Outer-Complexome Organization

Hundreds of different protein complexes that perform important functions across all cellular processes, collectively comprising the "complexome" of an organism, have been identified1. However, less is known about the fraction of the interactome that exists outside the complexome, in the "outer-complexome". To investigate features of "inner"- versus outer-complexome organisation in yeast, we generated a high-quality atlas of binary protein-protein interactions (PPIs), combining three previous maps2-4 and a new reference all-by-all binary interactome map. A greater proportion of interactions in our map are in the outer-complexome, in comparison to those found by affinity purification followed by mass spectrometry5-7 or in literature curated datasets8-11. In addition, recent advances in deep learning predictions of PPI structures12 mirror the existing experimentally resolved structures in being largely focused on the inner complexome and missing most interactions in the outer-complexome. Our new PPI network suggests that the outer-complexome contains considerably more PPIs than the inner-complexome, and integration with functional similarity networks13-15 reveals that interactions in the inner-complexome are highly detectable and correspond to pairs of proteins with high functional similarity, while proteins connected by more transient, harder-to-detect interactions in the outer-complexome, exhibit higher functional heterogeneity.

systems biology↗

A map of direct SARS-CoV-2 protein interactions implicates specific human host processes

Key steps in viral propagation, immune suppression, and pathology are mediated by direct, binary, physical interactions between viral and host proteins. To understand the biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we generated an unbiased systematic map of binary interactions between viral and host proteins, complementing previous co-complex association maps by conveying more direct mechanistic understanding and potentially enabling targeted disruption of direct interactions. To this end, we deployed two parallel strategies, identifying 205 virus-host and 27 intraviral binary interactions amongst 171 host and 19 viral proteins, and confirming high quality of these interactions via a calibrated orthogonal assay. Host proteins interacting with SARS-CoV-2 proteins are enriched in various cellular processes, including immune signaling and inflammation, protein ubiquitination, and membrane trafficking. Specific subnetworks provide new hypotheses related to viral modulation of host protein homeostasis and T-cell regulation. The binary virus-host protein interactions we identified can now be prioritized as targets for therapeutic intervention. More generally, we provide a resource of systematic maps describing which SARS-CoV-2 and human proteins interact directly.

systems biology↗

Polycomb suppresses a female gene regulatory network in Sertoli cells

Gonadal sex determination is controlled by the support cells of testes and ovaries. In testes, the epigenetic mechanism that maintains cellular memory to suppress female sexual differentiation remains unknown. Here, we show that Polycomb suppresses a female gene regulatory network in Sertoli cells, the specific support cells for postnatal testes. Through genetic ablation, we removed Polycomb repressive complex 1 (PRC1) from embryonic Sertoli cells after sex determination. PRC1-depleted postnatal Sertoli cells exhibited defective proliferation and cell death, leading to the degeneration of adult testes. In adult Sertoli cells, PRC1 suppressed the specific, critical genes required for granulosa cells, the support cells of ovaries, thereby inactivating the female gene regulatory network. The underlying chromatin of female genes was coated with Polycomb-mediated repressive modifications: PRC1-mediated H2AK119ub and PRC2-mediated H3K27me3. Taken together, we identify a critical mechanism centered on Polycomb that maintains the male fate in adult testes.

developmental biology↗

The viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape

While viral infections are known to hijack the transcription and translation of the host cell, the extent to which encoded viral proteins coordinate these perturbations remains unclear. Here we demonstrate that the oncoviral proteins Tax and HBZ interact with specific components of the spliceosome machinery, including the U2 auxiliary factor large subunit (U2AF2), and the complementary factor for APOBEC-1 (A1CF), respectively. Tax and HBZ perturb the splicing landscape in T-cells by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia (ATL) patients, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinately used by Tax and HBZ to reprogram the transcriptome. HighlightsO_LITax and HBZ interact with RNA-binding proteins as well as transcription factors C_LIO_LIHTLV-1 encoded proteins Tax and HBZ alter the splicing landscape in T-cells C_LIO_LITax and HBZ expression affect alternative splicing of 33 and 63 cancer genes, respectively C_LIO_LIOpposing roles for Tax and HBZ in deregulation of gene expression C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/427104v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@b5f6f0org.highwire.dtl.DTLVardef@6725b3org.highwire.dtl.DTLVardef@1dc32fborg.highwire.dtl.DTLVardef@19728c6_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

Exosomal melanotransferrin as a potential biomarker for metastatic melanoma

Cutaneous melanoma is the most lethal type of skin cancer. Early detection is crucial to improve the outcome of melanoma patients. The identification of noninvasive prognostic biomarkers for the follow-up of melanoma patients is still in demand for clinical use. We show here that exosomal melanotransferrin (MTf) fulfils the biomarker characteristics required to meet this demand. MTf is typically overexpressed in melanoma cells compared to other cell types - including cancer cells - and is efficiently sorted and secreted with nanovesicles, or so-called exosomes, due to its membrane-anchoring by a glycosylphosphatidylinositol. MTf is exposed on the surface of exosomes and is accessible for antibody recognition. An ELISA was set-up to quantify MTf after immobilization of nanovesicles through the exosomal constituent tetraspanins CD63. MTf was detected using low number of exosomes purified from melanoma cell line cultures, and MTf detection was abolished by phosphatidylinositol-specific phospholipase C (PI-PLC) treatment. This exosomal MTf ELISA was able to discriminate an equal number of assayed exosomes purified from two different melanoma cell lines (A-375 vs SK-MEL-28). Moreover, plasma samples from patients with melanoma and noncancer disease were assayed using this ELISA and exosomal MTf was validated as a potential melanoma biomarker.

cell biology↗

Comprehensive characterization of protein-protein interaction network perturbations by human disease mutations

Technological and computational advances in genomics and interactomics have made it possible to identify rapidly how disease mutations perturb interaction networks within human cells. In this study, we investigate at large-scale the effects of network perturbations caused by disease mutations within the human three-dimensional (3D), structurally-resolved macromolecular interactome. We show that disease-associated germline mutations are significantly enriched in sequences encoding protein-protein interfaces compared to mutations identified in healthy subjects from the 1000 Genomes and ExAC projects; these interface mutations correspond to protein-protein interaction (PPI)-perturbing alleles including p.Ser127Arg in PCSK9 at the PCSK9-LDLR interface. In addition, somatic missense mutations are significantly enriched in PPI interfaces compared to non-interfaces in 10,861 human exomes across 33 cancer subtypes/types from The Cancer Genome Atlas. Using a binomial statistical model, we computationally identified 470 PPIs harboring a statistically significant excess number of missense mutations at protein-protein interfaces (termed putative oncoPPIs) in pan-cancer analysis. We demonstrate that the oncoPPIs, including histone H4 complex in individual cancer types, are highly correlated with patient survival and drug resistance/sensitivity in human cancer cell lines and patient-derived xenografts. We experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay. We further showed that ALOX5 p.Met146Lys at the ALOX5-MAD1L1 interface and RXRA p.Ser427Phe at the RXRA-PPARG interface promote significant tumor cell growth using cell line-based functional assays, providing a functional proof-of-concept. In summary, if broadly applied, this human 3D interactome network analysis offers a powerful tool for prioritizing alleles with mutations altering PPIs that may contribute to the pathobiology of human diseases, and may offer disease-specific targets for genotype-informed therapeutic discovery.

systems biology↗

Exostosin-1 Glycosyltransferase Regulates Endoplasmic Reticulum Architecture and Dynamics

The endoplasmic reticulum (ER) is a central eukaryotic organelle with a tubular network made of hairpin proteins linked by hydrolysis of GTP nucleotides. Among post-translational modifications initiated at the ER level, glycosylation is the most common reaction. However, our understanding of the impact of glycosylation on ER structure remains unclear. Here, we show that Exostosin-1 (EXT1) glycosyltransferase, an enzyme involved in N-glycosylation, is a key regulator of ER morphology and dynamics. We have integrated multi-omics data and super-resolution imaging to characterize the broad effect of EXT1 inactivation, including ER shape-dynamics-function relationships in mammalian cells. We have observed that, inactivating EXT1 induces cell enlargement and enhances metabolic switches such as protein secretion. In particular, suppressing EXT1 in mouse thymocytes causes developmental dysfunctions associated to ER network extension. Our findings suggest that EXT1 drives glycosylation reactions involving ER structural proteins and high-energy nucleotide sugars, which might also apply to other organelles.

cell biology↗

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

The worldwide SARS-CoV-2 outbreak poses a serious challenge to human societies and economies. SARS-CoV-2 proteins orchestrate complex pathogenic mechanisms that underlie COVID-19 disease. Thus, understanding how viral polypeptides rewire host protein networks enables better-founded therapeutic research. In complement to existing proteomic studies, in this study we define the first proximal interaction network of SARS-CoV-2 proteins, at the whole proteome level in human cells. Applying a proximity-dependent biotinylation (BioID)-based approach greatly expanded the current knowledge by detecting interactions within poorly soluble compartments, transient, and/or of weak affinity in living cells. Our BioID study was complemented by a stringent filtering and uncovered 2,128 unique cellular targets (1,717 not previously associated with SARS-CoV-1 or 2 proteins) connected to the N- and C-ter BioID-tagged 28 SARS-CoV-2 proteins by a total of 5,415 (5,236 new) proximal interactions. In order to facilitate data exploitation, an innovative interactive 3D web interface was developed to allow customized analysis and exploration of the landscape of interactions (accessible at http://www.sars-cov-2-interactome.org/). Interestingly, 342 membrane proteins including interferon and interleukin pathways factors, were associated with specific viral proteins. We uncovered ORF7a and ORF7b protein proximal partners that could be related to anosmia and ageusia symptoms. Moreover, comparing proximal interactomes in basal and infection-mimicking conditions (poly(I:C) treatment) allowed us to detect novel links with major antiviral response pathway components, such as ORF9b with MAVS and ISG20; N with PKR and TARB2; NSP2 with RIG-I and STAT1; NSP16 with PARP9-DTX3L. Altogether, our study provides an unprecedented comprehensive resource for understanding how SARS-CoV-2 proteins orchestrate host proteome remodeling and innate immune response evasion, which can inform development of targeted therapeutic strategies.

systems biology↗

Reduced placental transfer of antibodies against microbial and vaccine antigens in HIV-infected women in Mozambique

Antibody transplacental transfer is essential for conferring protection in newborns against infectious diseases. This transfer may be affected by gestational age and maternal infections, although the effects are not consistent across studies. We measured total IgG and IgG subclasses by quantitative suspension array technology against fourteen pathogens and vaccine antigens, including target of maternal immunization, in 341 delivering HIV- and HIV+ mother-infant pairs from southern Mozambique. Maternal antibody levels were the main determinant of cord antibody levels. HIV broadly reduced the placental transfer and cord levels of IgG and IgG1, but also IgG2 to half of the antigens. Plasmodium falciparum exposure and prematurity were negatively associated with cord antibody levels and placental transfer but this was antigen-subclass dependent. These findings suggest maternal infections may impact the efficacy of maternal immunization and confirm the lower transfer of antibodies as one of the causes underlying increased susceptibility to infections in HIV-exposed infants.

immunology↗

Highly sensitive and specific multiplex antibody assays to quantify immunoglobulins M, A and G against SARS-CoV-2 antigens

Reliable serological tests are required to determine the prevalence of antibodies against SARS-CoV-2 antigens and to characterise immunity to the disease in order to address key knowledge gaps in the context of the COVID-19 pandemic. Quantitative suspension array technology (qSAT) assays based on the xMAP Luminex platform overcome the limitations of rapid diagnostic tests and ELISA with their higher precision, dynamic range, throughput, miniaturization, cost-efficacy and multiplexing capacity. We developed three qSAT assays to detect IgM, IgA and IgG to a panel of eight SARS-CoV-2 antigens including spike (S), nucleoprotein (N) and membrane (M) protein constructs. The assays were optimized to minimize processing time and maximize signal to noise ratio. We evaluated the performance of the assays using 128 plasmas obtained before the COVID-19 pandemic (negative controls) and 115 plasmas from individuals with SARS-CoV-2 diagnosis (positive controls), of whom 8 were asymptomatic, 58 had mild symptoms and 49 were hospitalized. Pre-existing IgG antibodies recognizing N, M and S2 proteins were detected in negative controls suggestive of cross-reactive to common cold coronaviruses. The best performing antibody isotype/antigen signatures had specificities of 100% and sensitivities of 94.94% at [≥]14 days since the onset of symptoms and 96.08% at [≥]21 days since the onset of symptoms, with AUC of 0.992 and 0.999, respectively. Combining multiple antibody markers as assessed by qSAT assays has the highest efficiency, breadth and versatility to accurately detect low-level antibody responses for obtaining reliable data on prevalence of exposure to novel pathogens in a population. Our assays will allow gaining insights into antibody correlates of immunity required for vaccine development to combat pandemics like the COVID-19.

immunology↗