Biology subjects

Caron, E.

Publications and source records attributed to Caron, E..

At least 19 recordsLinked to original sources

bioRxiv2026

Epistatic evolution drives HLA-dependent CD8+ T Cell escape risk in diverse populations

Understanding how viral evolution shapes HLA-dependent T cell escape is crucial to identify individuals at risk of reduced cellular immunity to emerging variants. Nevertheless, we lack frameworks to model HLA diversity and the evolutionary feasibility of T cell-evading mutations. Here, we construct an HLA map capturing variation in epitope specificity across HLA-typed cohorts. Enhancing this framework with SARS-CoV-2 CD8 T cell escape reveals heterogeneous escape across HLA-defined groups, with clusters enriched for HLA-B*07:02, HLA-A*03:01 and HLA-A*02:01 showing higher epitope loss. To assess the evolutionary plausibility of escape, we model viral sequence fitness using an epistasis-aware protein language approach trained on coronaviruses to systematically score mutations across viral lineages. We find that the fitness effect of mutations dynamically changes with evolving sequence context, and that T cell-evading mutations become fitter with additional escape mutations. This study links host HLA diversity to viral fitness landscapes for surveillance and vaccine design.

genomics↗

bioRxiv2026

Benchmarking generative scaffold design methods for peptide engineering in TCR-MHC complexes

De novo peptide design at T cell receptor-peptide-major histocompatibility complex (TCR-pMHC) interfaces is a central challenge in computational immunology, with direct implications for vaccine development, cancer immunotherapy, and autoimmune disease. Despite rapid advances in generative protein modeling, there is currently no systematic benchmark evaluating these methods in the highly constrained and immunologically relevant setting of peptide-MHC presentation and TCR recognition. Here, we present two complementary contributions. First, we introduce a multi-stage computational pipeline for peptide design in predefined TCR-pMHC contexts, integrating generative modeling with sequence optimization and structure-based filtering. Second, we establish a benchmark for evaluating generative peptide design methods in TCR-pMHC complexes. Using a curated dataset of high-quality crystal structures deposited after the AlphaFold3 training cutoff, we assess state-of-the-art generative approaches for peptide backbone generation, sequence design, and the enrichment of near-native solutions. We explicitly examine whether different backbone generation strategies respect the geometric constraints of the MHC binding groove and recover native-like peptide conformations. Our results reveal substantial method-dependent differences: some generative strategies fail systematically in the groove-bound peptide setting, whereas others generate physically plausible backbones with varying accuracy and conformational diversity. We further show that enforcing anchor constraints strongly influences peptide conformations at non-anchor positions, highlighting a trade-off between structural accuracy and conformational sampling. To enable fair and reproducible comparison, we introduce a standardized, multi-stage scoring protocol that integrates MHC binding prediction, physics-based energy evaluation, and independent structure prediction confidence metrics to enrich near-native designs from large candidate pools. Together, this work establishes the first comprehensive pipeline and benchmark for generative peptide design at TCR-pMHC interfaces and provides practical guidelines for developing peptide design workflows and evaluating generative models in immunologically constrained protein design settings.

bioinformatics↗

bioRxiv2025

No Evidence of Direct Activation of Human Neutrophil Responses by Multivalent Prefusion Trimeric SARS-CoV-2 Spike Protein ex vivo

The SARS-CoV-2 Spike (S) protein is essential for viral entry and serves as the primary immunogen in most COVID-19 vaccines. While its role in adaptive immunity is well defined, its potential to contribute directly to innate immune activation and remains incompletely understood. Neutrophils, in particular, are prominent effectors in COVID-19 severity, yet how they respond directly to the S protein presented in a multivalent format is unclear. Here, we investigated whether the S protein can directly activate human neutrophils ex vivo using two biologically relevant models: nanoparticles displaying multivalent stabilized prefusion trimeric S glycoprotein, and purified {beta}-propiolactone-inactivated SARS-CoV-2 virions. Neutrophils were exposed to nanoparticles or inactivated virus, either alone or pre-coated with monoclonal or polyclonal anti-S antibodies. Nanoparticles displaying Respiratory Syncytial Virus (RSV) Fusion (F) protein and purified {beta}-propiolactone-inactivated RSV served as comparators. Across all models and conditions tested, the S protein did not induce significant neutrophil responses. No consistent effects were observed on cell viability, surface marker expression, reactive oxygen species production, neutrophil extracellular trap formation, cytokine release, or inflammatory gene expression--even in the presence of anti-S antibodies mimicking immune complexes. Results with F-nanoparticles and inactivated RSV were similarly modest. These findings indicate that the trimeric prefusion S protein, whether displayed multivalently on nanoparticles or in the context of inactivated viral particles, is insufficient to trigger robust neutrophil activation. This work provides insight into the innate immune profile of the S protein and suggests that its use in vaccine platforms is unlikely to directly provoke neutrophil-mediated inflammatory responses.

immunology↗

bioRxiv2025

Vesicle-mediated oxytocin release drives melanocortin circuit maturation during a neonatal critical period

The hypothalamus is crucial for regulating essential bodily functions, including energy balance. It is an exceedingly complex and heterogeneous brain region that contains a variety of neuronal systems that are interconnected with each other. Among these, the melanocortin system, which comprises pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons, displays a remarkable anatomical relationship with oxytocin (OT) neurons in the paraventricular nucleus (PVH). Here, we demonstrate that OT neurons are instrumental in the development of the melanocortin system. Chemogenetic inhibition of OT neurons during the first postnatal week selectively disrupts POMC and AgRP projections to the PVH, without affecting other target nuclei like the dorsomedial nucleus. This developmental role is age-dependent, as silencing OT neurons in juvenile or adult stages has no impact on melanocortin circuits. OT neurons release various neuropeptides and neurotransmitters, and their secretion can be modulated by chemogenetic manipulation. Expressing the botulinum toxin serotype B light chain in OT neurons reveals that their developmental actions rely on SNARE-mediated exocytosis. Moreover, administering an OT receptor antagonist during the first postnatal week leads to similar melanocortin circuit defects and long-term metabolic effects. Furthermore, neonatal chemogenetic activation of OT neurons rescues POMC circuit deficits in a mouse model of Prader-Willi Syndrome. These findings reveal that OT acts as a paracrine neurotrophic factor orchestrating the development of melanocortin circuits during a restricted neonatal critical period.

neuroscience↗

bioRxiv2024

ImmunoStruct: Integration of protein sequence, structure, and biochemical properties for immunogenicity prediction and interpretation

Epitope-based vaccines are promising therapeutic modalities for infectious diseases and cancer, but identifying immunogenic epitopes is challenging. The vast majority of prediction methods only use amino acid sequence information, and do not incorporate wide-scale structure data and biochemical properties across each peptide-MHC. We present ImmunoStruct, a deep-learning model that integrates sequence, structural, and biochemical information to predict multi-allele class-I peptide-MHC immunogenicity. By leveraging a multimodal dataset of[~] 27,000 peptide-MHCs, we demonstrate that ImmunoStruct improves immunogenicity prediction performance and interpretability beyond existing methods, across infectious disease epitopes and cancer neoepitopes. We further show strong alignment with in vitro assay results for a set of SARS-CoV-2 epitopes, as well as strong performance in peptide-MHC-based cancer patient survival prediction. Overall, this work also presents a new architecture that incorporates equivariant graph processing and multimodal data integration for the long standing task in immunotherapy.

immunology↗

bioRxiv2024

Investigation of a Novel Mouse Model of Prader-Willi Syndrome with Invalidation of Necdin and Magel2

Prader-Willi syndrome (PWS) is a multigenic disorder caused by the loss of seven contiguous paternally expressed genes. Mouse models with inactivation of all PWS genes are lethal. Knockout (KO) mouse models for each candidate gene were generated, but they lack the functional interactions between PWS genes. Here, we revealed an interplay between Necdin and Magel2 "PWS" genes and generated a novel mouse model (named "Madin") with a deletion including both genes. A subset of Madin KO mice showed neonatal lethality. Behaviorally, surviving mutant mice exhibited sensory delays during infancy and alterations in social exploration at adulthood. Madin KO mice had a lower body weight before weaning, persisting after weaning in males only, with reduced fat mass and improved glucose tolerance. Delayed sexual maturation and altered timing of puberty onset were observed in mutant mice. Adult Madin KO mice displayed increased ventilation and a persistent increase in apneas following a hypercapnic challenge. Transcriptomics analyses revealed a dysregulation of key circadian genes and alterations of genes associated with axonal function that were also found in the hypothalamus of patients with PWS. At neuroanatomical levels, we report an impaired maturation of oxytocin neurons and a disrupted development of melanocortin circuits. Together, these data indicate that the Madin KO mouse is a reliable and more genetically relevant model for the study of PWS.

systems biology↗

bioRxiv2023

WEGS: a cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome

0Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a novel, cost-effective method, which we call "Whole Exome Genome Sequencing" (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed). We experimentally assess the performance of WEGS with four different depth of coverage and sample multiplexing configurations. We show that the optimal WEGS configurations are 1.7-2.0 times cheaper than standard WES (no-plexing), 1.8-2.1 times cheaper than high-depth WGS, reach similar recall and precision rates in detecting coding variants as WES, and capture more population-specific variants in the rest of the genome that are difficult to recover when using genotype imputation methods. We apply WEGS to 862 patients with peripheral artery disease and show that it directly assesses more known disease-associated variants than a typical genotyping array and thousands of non-imputable variants per disease-associated locus.

genomics↗

bioRxiv2022

Integrated Immunopeptidomics and Proteomics Study Reveals Imbalanced Innate and Adaptive Immune Responses to SARS-Cov-2 Infection

We present an integrated immunopeptidomics and proteomics study of SARS-Cov-2 infection to comprehensively decipher the changes in host cells in response to viral infection. Our results indicated that innate immune response in Calu-3 cells was initiated by TLR3, followed by activation of interferon signaling pathway. Host cells also present viral antigens to the cell surface through both Class I and Class II MHC system for recognition by adaptive immune system. SARS-Cov-2 infection led to the disruption of antigen presentation as demonstrated by higher level of HLA proteins from the flow-through of MHC immunoprecipitation. Glycosylation analysis of HLA proteins from the elution and flow-through of immunoprecipitation revealed that the synthesis and degradation of HLA protein was affected by SARS-Cov-2 infection. This study provided many useful information to study the host response to SARS-Cov-2 infection and would be helpful for the development of therapeutics and vaccine for Covid-19 and future pandemic.

immunology↗

bioRxiv2022

Induction of senescence renders cancer cells highly immunogenic

Cellular senescence is a stress response that activates innate immunity. However, the interplay between senescent cells and the adaptive immune system remains largely unexplored. Here, we show that senescent cells display enhanced MHC class I (MHC-I) antigen processing and presentation. Immunization of mice with senescent syngeneic fibroblasts generates CD8 T cells reactive against both normal and senescent fibroblasts, some of them targeting senescence-associated MHC-I-peptides. In the context of cancer, we demonstrate that senescent cancer cells trigger strong anti-tumor protection mediated by antigen-presenting cells and CD8 T cells. This response is superior to the protection elicited by cells undergoing immunogenic cell death. Finally, induction of senescence in patient-derived cancer cells exacerbates the activation of autologous tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs) with no effect on non-reactive TILs. Our study indicates that immunization with senescent cancer cells strongly activates anti-tumor immunity, and this can be exploited for cancer therapy. STATEMENT OF SIGNIFICANCEOur study shows that senescent cells are endowed with a high immunogenic potential, superior to the gold standard of immunogenic cell death. The induction of senescence in cancer cells can be exploited to develop efficient and protective CD8-dependent anti-tumor immune responses.

cancer biology↗

bioRxiv2021

Data-driven approaches for genetic characterization of SARS-CoV-2 lineages

The genome of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19), has been sequenced at an unprecedented scale, leading to a tremendous amount of viral genome sequencing data. To understand the evolution of this virus in humans, and to assist in tracing infection pathways and designing preventive strategies, we present a set of computational tools that span phylogenomics, population genetics and machine learning approaches. To illustrate the utility of this toolbox, we detail an in depth analysis of the genetic diversity of SARS-CoV-2 in first year of the COVID-19 pandemic, using 329,854 high-quality consensus sequences published in the GISAID database during the pre-vaccination phase. We demonstrate that, compared to standard phylogenetic approaches, haplotype networks can be computed efficiently on much larger datasets, enabling real-time analyses. Furthermore, time series change of Tajimas D provides a powerful metric of population expansion. Unsupervised learning techniques further highlight key steps in variant detection and facilitate the study of the role of this genomic variation in the context of SARS-CoV-2 infection, with Multiscale PHATE methodology identifying fine-scale structure in the SARS-CoV-2 genetic data that underlies the emergence of key lineages. The computational framework presented here is useful for real-time genomic surveillance of SARS-CoV-2 and could be applied to any pathogen that threatens the health of worldwide populations of humans and other organisms.

bioinformatics↗

bioRxiv2021

The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

The rapid, global dispersion of SARS-CoV-2 since its initial identification in December 2019 has led to the emergence of a diverse range of variants. The initial concerns regarding the virus were quickly compounded with concerns relating to the impact of its mutated forms on viral infectivity, pathogenicity and immunogenicity. To address the latter, we seek to understand how the mutational landscape of SARS-CoV-2 has shaped HLA-restricted T cell immunity at the population level during the first year of the pandemic, before mass vaccination. We analyzed a total of 330,246 high quality SARS-CoV-2 genome assemblies sampled across 143 countries and all major continents. Strikingly, we found that specific mutational patterns in SARS-CoV-2 diversify T cell epitopes in an HLA supertype-dependent manner. In fact, we observed that proline residues are preferentially removed from the proteome of prevalent mutants, leading to a predicted global loss of SARS-CoV-2 T cell epitopes in individuals expressing HLA-B alleles of the B7 supertype family. In addition, we show that this predicted global loss of epitopes is largely driven by a dominant C-to-U mutation type at the RNA level. These results indicate that B7 supertype-associated epitopes, including the most immunodominant ones, were more likely to escape CD8+ T cell immunosurveillance during the first year of the pandemic. Together, our study lays the foundation to help understand how SARS-CoV-2 mutants shape the repertoire of T cell targets and T cell immunity across human populations. The proposed theoretical framework has implications in viral evolution, disease severity, vaccine resistance and herd immunity.

immunology↗

bioRxiv2021

A crosstalk between E2F1 and GLP-1 signaling pathways modulates insulin secretion

Compromised {beta}-cell function contributes to type 2 diabetes (T2D) development. The glucagon like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential toward T2D treatment, notably by improving {beta}-cell functions. Recent data have shown that the transcription factor E2f1, besides its role as a cell cycle regulator, is involved in glucose homeostasis by modulating {beta}-cell mass, function and identity. Here, we demonstrate a crosstalk between the E2F1, phosphorylation of retinoblastoma protein (pRb) and Glp-1 signaling pathways. We found that {beta}-cell specific E2f1 deficient mice (E2f1{beta}-/-) presented with impaired glucose homeostasis and decreased glucose stimulated-insulin secretion mediated by exendin 4 (i.e., GLP1R agonist), which were associated with decreased expression of Glp1r encoding Glp-1 receptor (GLP1R) in E2f1{beta}-/- pancreatic islets. Decreasing E2F1 transcriptional activity with an E2F inhibitor in islets from nondiabetic humans decreased GLP1R levels and blunted the incretin effect of exendin 4 on insulin secretion. Conversely, overexpressing E2f1 in pancreatic {beta} cells increased Glp1r expression associated with enhanced insulin secretion mediated by GLP1R agonist. Interestingly, kinome analysis of mouse islets demonstrated that an acute treatment with exendin 4 increased pRb phosphorylation and subsequent E2f1 transcriptional activity. This study suggests a molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways that modulates insulin secretion and glucose homeostasis.

physiology↗

bioRxiv2020

Immunopeptidomics for Dummies: Detailed Experimental Protocols and Rapid, User-Friendly Visualization of MHC I and II Ligand Datasets with MhcVizPipe

Immunopeptidomics refers to the science of investigating the composition and dynamics of peptides presented by major histocompatibility complex (MHC) class I and class II molecules using mass spectrometry (MS). Here, we aim to provide a technical report to any non-expert in the field wishing to establish and/or optimize an immunopeptidomic workflow with relatively limited computational knowledge and resources. To this end, we thoroughly describe step-by-step instructions to isolate MHC class I and II-associated peptides from various biological sources, including mouse and human biospecimens. Most notably, we created MhcVizPipe (MVP) (https://github.com/CaronLab/MhcVizPipe), a new and easy-to-use open-source software tool to rapidly assess the quality and the specific enrichment of immunopeptidomic datasets upon the establishment of new workflows. In fact, MVP enables intuitive visualization of multiple immunopeptidomic datasets upon testing sample preparation protocols and new antibodies for the isolation of MHC class I and II peptides. In addition, MVP enables the identification of unexpected binding motifs and facilitates the analysis of non-canonical MHC peptides. We anticipate that the experimental and bioinformatic resources provided herein will represent a great starting point for any non-expert and will therefore foster the accessibility and expansion of the field to ultimately boost its maturity and impact.

bioinformatics↗

bioRxiv2020

The Global Architecture Shaping the Heterogeneity and Tissue-Dependency of the MHC Class I Immunopeptidome is Evolutionarily Conserved

Understanding the molecular principles that govern the composition of the mammalian MHC-I immunopeptidome (MHC-Ii) across different primary tissues is fundamentally important to predict how T cell respond in different contexts in vivo. Here, we performed a global analysis of the mammalian MHC-Ii from 29 and 19 primary human and mouse tissues, respectively. First, we observed that different HLA-A, -B and -C allotypes do not contribute evenly to the global composition of the MHC-Ii across multiple human tissues. Second, we found that peptides that are presented in a tissue-dependent and -independent manner share very distinct properties. Third, we discovered that proteins that are evolutionarily hyperconserved represent the primary source of the MHC-Ii at the organism-wide scale. Finally, we uncovered new components of the antigen processing and presentation network that may drive the high level of heterogeneity of the MHC-Ii across different tissues in mammals. This study opens up new avenues toward a system-wide understanding of antigen presentation in vivo and may serve as ground work to understand tissue-dependent T cell responses in autoimmunity, infectious diseases and cancer.

immunology↗

bioRxiv2020

Pinpointing of cysteine oxidation sites in vivo by high-resolution proteomics reveals mechanism of redox-dependent inhibition of STING

Protein function is regulated by post-translational modifications, among which reversible oxidation of Cys (Cys ox-PTM) emerged as a key regulatory mechanism of cellular responses. The redox regulation of virus-host interactions is well documented, but in most cases, proteins subjected to Cys ox-PTM remain unknown. The identification of Cys ox-PTM sites in vivo is essential to underpin our understanding of the mechanisms of the redox regulation. In this study, we present a proteome-wide identification of reversible Cys ox-PTM sites in vivo during stimulation by oxidants using a maleimide-based bioswitch method coupled to mass spectrometry. We identified 2720 unique Cys ox-PTM sites encompassing 1473 proteins with distinct abundance, location and functions. Label-free quantification (LFQ)-based analysis revealed the enrichment of ox-PTM in numerous pathways, many relevant to virus-host interaction. Here, we focused on the oxidation of STING, the central adaptor of the innate immune type I interferon pathway induced upon detection of cytosolic DNA. We provide the first in vivo demonstration of reversible oxidation of Cys148 and Cys206 of STING. Molecular analyses led us to establish a new model in which Cys148 oxidation is constitutive, while Cys206 oxidation is inducible by oxidative stress or by the natural ligand 23-cGAMP. We show that oxidation of Cys206 has an inhibitory function to prevent STING hyperactivation through the constraint of a conformational change associated with the formation of inactive polymers containing intermolecular disulfide bonds. This provides new ground for the design of therapies targeting STING relevant to autoinflammatory disorders, immunotherapies and vaccines. Brief summary of the main resultsThe function of proteins is regulated by post-translational modifications, among which reversible oxidation of Cys recently emerged as a key component. Comprehension of redox regulation of cellular responses requires identification of specific oxidation sites in vivo. Using a bioswitch method to specifically label Cys subjected to reversible oxidation coupled to mass spectrometry, we identified thousands of novel oxidation sites. Many are relevant to virus-host interaction pathways. Here, we focused on the oxidation of STING, an adaptor critical for activating the innate immune type I interferon pathway engaged upon cytosolic DNA sensing. Molecular studies led us to establish a new model in which STING Cys148 is oxidized at basal levels, while Cys206 oxidation is induced by oxidative stress and ligand binding. We show that oxidation of Cys206 has an inhibitory function to prevent STING hyperactivation. This study provides ground for novel research avenues aimed at designing therapeutics that target this pathway.

immunology↗

bioRxiv2019

The E3 ubiquitin ligase TRAF6 is a novel interacting protein of amyotrophic lateral sclerosis-linked misfolded SOD1

Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the selective loss of motor neurons leading to paralysis. Mutations in the gene encoding superoxide dismutase 1 (SOD1) are the second most common cause of familial ALS, and considerable evidence suggests that these mutations result in an increase in toxicity due to protein misfolding. We previously demonstrated in the SOD1G93A rat model that misfolded SOD1 exists as distinct conformers and forms deposits on mitochondrial subpopulations. Here, using SOD1G93A rats and conformation-restricted antibodies specific for misfolded SOD1 (B8H10 and AMF7-63), we identified the interactomes of the mitochondrial pools of misfolded SOD1. This strategy identified binding proteins that uniquely interacted with either AMF7-63 or B8H10-reactive SOD1 conformers as well as with a high proportion of interactors common to both conformers. Of this latter set, we identified the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) as a SOD1 interactor and determined that exposure of the SOD1 functional loops facilitates this interaction. Of note, this conformational change was not universally fulfilled by all SOD1 variants and differentiated TRAF6-interacting from TRAF6 non-interacting SOD1 variants. Functionally, TRAF6 stimulated polyubiquitination and aggregation of the interacting SOD1 variants. TRAF6 E3 ubiquitin ligase activity was required for the former, but was dispensable for the latter, indicating that TRAF6-mediated polyubiquitination and aggregation of the SOD1 variants are independent events. We propose that the interaction between misfolded SOD1 and TRAF6 may be relevant to the etiology of ALS.

neuroscience↗

bioRxiv2018

RNASeq analysis identifies non-canonical role of STAT2 and IRF9 in the regulation of a STAT1-independent antiviral and immunoregulatory transcriptional program induced by IFNβ and TNFα

IFN{beta} typically induces an antiviral and immunoregulatory transcriptional program through the activation of ISGF3 (STAT1, STAT2 and IRF9) transcriptional complexes. The response to IFN{beta} is context-dependent and is prone to crosstalk with other cytokines, such as TNF IFN{beta} and TNF synergize to drive a specific delayed transcriptional program. Previous observation led to the hypothesis that an alternative STAT1-independent pathway involving STAT2 and IRF9 might be involved in gene induction by the combination of IFN{beta} and TNF. Using genome wide transcriptional profiling by RNASeq, we found that the costimulation with IFN{beta} and TNF induces a broad antiviral and immunoregulatory transcriptional program independently of STAT1. Additionally, STAT2 and IRF9 are involved in the regulation of only a subset of these STAT1-independent genes. Consistent with the growing literature, STAT2 and IRF9 act in concert to regulate a subgroup of these genes. Unexpectedly, STAT2 and IRF9 were also engaged in specific independent pathways to regulate distinct sets of IFN{beta} and TNF-induced genes. Altogether these observations highlight the existence of distinct previously unrecognized non-canonical STAT1-independent, but STAT2 and/or IRF9-dependent pathways in the establishment of a delayed antiviral and immunoregulatory transcriptional program in conditions where elevated levels of both IFN{beta} and TNF are present.

immunology↗

bioRxiv2017

DUSP1 promotes apoptosis and suppresses cell migration, while leaving the JIP1-protected cytokine production intact, during paramyxovirus infection.

The host antiviral response involves the induction of interferons and proinflammatory cytokines, but also the activation of cell death pathways, including apoptosis, to limit viral replication and spreading. This host defense is strictly regulated to eliminate the infection while limiting tissue damage that is associated with virus pathogenesis. Post-translational modifications, most notably phosphorylation, are key regulators of the antiviral defense implying an important role of protein phosphatases. Here, we investigated the role of the dual-specificity phosphatase 1 (DUSP1) in the host defense against human respiratory syncytial virus (RSV), a pathogenic virus of the Pneumoviridae family, and Sendai virus (SeV), a model virus being developed as a vector for anti-RSV vaccine. We found that DUSP1 is upregulated before being subjected to proteasomal degradation. DUSP1 does not inhibit the antiviral response, but negatively regulates virus-induced JNK/p38 MAPK phosphorylation. Interaction with the JNK-interacting protein 1 scaffold protein prevents dephosphorylation of JNK by DUSP1, likely explaining that AP-1 activation and downstream cytokine production are protected from DUSP1 inhibition. Importantly, DUSP1 promotes SeV-induced apoptosis and suppresses cell migration in RSV-infected cells. Collectively, our data unveil a previously unrecognized selective role of DUSP1 in the regulation of tissue damage and repair during infections by RSV and SeV.

microbiology↗