Biology subjects

Chaloin, L.

Publications and source records attributed to Chaloin, L..

7 recordsLinked to original sources

bioRxiv2026

Neurobiological alterations and autism-like phenotype in mice following regulatory-limit exposure to fungicides in drinking water

Neurodevelopmental conditions, including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD), have increased markedly over recent decades. This rise parallels the widespread use of agrochemicals, suggesting a contribution of environmental exposures. We hypothesize that pesticide residues may disrupt brain development and promote neurodevelopmental disorders. Here, we test whether concentrations permitted in drinking water affect brain development using a maternal exposure model in wild-type mice. Exposure to a fungicide mixture at 0.3 g/L, below the current European regulatory limit of 0.5 g/L, impairs corticogenesis and is associated with alterations in synaptic function and glutamatergic signaling. Offspring exhibit delays in sensory development, reduced social interactions, and increased stereotyped behaviors. We identify the adenosine A2A receptor as a molecular target of anilinopyrimidine fungicides. Together, these findings indicate that low-dose exposure to this fungicide mixture can induce an autism spectrum-like phenotype in the offspring.

neuroscience↗

bioRxiv2026

A new HIV-1 latency reversing agent activating HIV-Tat

Despite its efficiency to prevent viral multiplication, antiretroviral therapy does not affect HIV-1 latently-infected cells. These cells do not produce significant amounts of viruses and constitute HIV-1 reservoir. To purge this long-lived viral reservoir, the "shock and kill" strategy relies on the use of latency reversing agents (LRAs) to induce activation of latent cells. All LRAs developed until now target cellular proteins and are therefore not specific for HIV-infected cells. Here we present a new LRA that binds and activates HIV-1 Tat which is the key regulator for viral transcription and latency reversal. This molecule termed D10 was designed to bind to the major groove of the Tat protein, and found to activate Tat transcriptional activity by stabilizing the HIV transcription complex. This LRA induces strong HIV production by latent cell lines and latent cells from people living with HIV-1. On latent cells from PBMCs, D10 is active at [~]50 nM, the concentration required to stabilize HIV transcription complex. D10 is the first Tat activator available and the first LRA that targets an HIV protein.

microbiology↗

bioRxiv2025

Syk activation during FcγR-mediated phagocytosis involves Syk palmitoylation and desulfenylation

The non-receptor Spleen tyrosine kinase Syk acts downstream of several receptors of the immune system such as the Fc{gamma}R. Syk is composed of a kinase domain and two SH2 domains that interact with the bi- phosphorylated ITAMs motifs of the Fc{gamma}R upon phagocytosis. This results in the activation of Syk by auto- phosphorylation, triggering phosphorylation of several downstream targets in a process that will culminate in F-actin polymerization and phagocytosis of the IgG-opsonized target. We found that Syk is S-acylated upon phagocytosis by macrophages. Palmitoylation is performed on a single Syk-Cys by the protein S-acyl transferase DHHC5 that specifically associates with Syk upon phagocytosis. Syk palmitoylation is required for Syk localization to the phagocytic cup, Syk phosphorylation/activation, Cdc42 recruitment to the cup, F-actin polymerization and phagocytosis. We also observed that another Syk-Cys residue is modified by sulfenylation. Mutation of the sulfenylated Cys that belongs to a redox-motif inactivated the Syk catalytic activity and phagocytosis. We found that Syk desulfenylation occurs during phagocytosis. Molecular dynamics studies indicated that desulfenylation increased the mobility and exposure of a loop within the Syk interdomain B, likely facilitating phosphorylation of key Syk-Tyr residues by upstream effectors such as Src kinases. We thus propose an original updated model for Syk activation during Fc{gamma}R-mediated phagocytosis that involves both Syk palmitoylation and desulfenylation.

cell biology↗

bioRxiv2024

Subtle changes at the RBD/hACE2 interface during SARS-CoV2 variant evolution: a molecular dynamics study

The SARS-CoV-2 Omicron variants present a different behavior compared to the previous variants, all particularly in respect to the Delta variant, as it seems to promote a lower morbidity although being much more contagious. In this perspective, we performed new molecular dynamics (MD) simulations of the various spike RBD/hACE2 complexes corresponding to the WT, Delta and Omicron variants (BA.1 up to BA.4/5) over 1.5 {micro}s timescale. Then, carrying out a comprehensive analysis of residue interactions within and between the two partners, allowed us to draw the profile of each variant by using complementary methods (PairInt, hydrophobic potential, contact PCA). Main results of PairInt calculations highlighted the most involved residues in electrostatic interactions that represent a strong contribution in the binding with highly stable contacts between spike RBD and hACE2 (importance of mutated residues at positions 417, 493 and 498). In addition to the swappable arginine residues (493/498), the apolar contacts made a substantial and complementary contribution in Omicron with the detection of two hydrophobic patches, one of which was correlated with energetic contribution calculations. This study brings new highlights on the global dynamics of spike RBD/hACE2 complexes resulting from the analysis of contact networks and cross-correlation matrices able to detect subtle changes at point mutations. The results of our study are also consistent with alternative approaches such as binding free energy calculations but are more informative and sensitive to transient or low-energy interactions. Nevertheless, the energetic contributions of residues at positions 501 and 505 were in good agreement with hydrophobic interactions measurements. The contact PCA networks could identify the intramolecular incidence of the S375F mutation occurring in all Omicron variants and likely conferring them an advantage in binding stability. Collectively, these data revealed the major differences observed between WT/Delta and Omicron variants at the RBD/hACE2 interface, which may explain the greater persistence of Omicron. Author SummaryThe evolution of SARS-CoV-2 was extremely rapid, leading to the global predominance of Omicron variants, despite the many mutations identified in the spike protein. Some of these were introduced to evade the immune system, but many others were located in the Receptor Binding Domain (RBD) without affecting its efficient binding to hACE2 and preserving the high infectivity of this variant. To unravel the mechanism by which this protein-protein connection remains strong or stable, it is necessary to study the different types of interactions at the atomic level and over time using molecular dynamics (MD) simulations. Indeed, in contrast to crystal or cryo-EM structures providing only a fixed image of the binding process, MD simulations have allowed to unambiguously identify the sustainability of some interactions mediated by key residues of spike RBD. This study could also highlight the interchangeable role of certain residues in compensating for a mutation, which in turn allows the virus to maintain durable binding to the host cell receptor. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/628120v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@b2a6c4org.highwire.dtl.DTLVardef@e29044org.highwire.dtl.DTLVardef@6d9835org.highwire.dtl.DTLVardef@123c6f9_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

bioinformatics↗

bioRxiv2022

Structural basis of the mycobacterial stress-response RNA polymerase auto-inhibition via oligomerization

Self-assembly of macromolecules into higher-order symmetric structures is fundamental for the regulation of biological processes. Higher-order symmetric structure self-assembly by the gene expression machinery, such as bacterial DNA-dependent RNA polymerase (RNAP), has never been reported before. Here, we show that the stress-response {sigma}B factor from the human pathogen, Mycobacterium tuberculosis, induces the RNAP holoenzyme oligomerization into a supramolecular complex composed of eight RNAP units. Cryo-electron microscopy revealed a pseudo-symmetric structure of the RNAP octamer in which RNAP protomers are captured in an auto-inhibited state and display an open-clamp conformation. The structure shows that {sigma}B is sequestered by the RNAP flap and clamp domains. The transcriptional activator RbpA prevented octamer formation by promoting the initiation-competent RNAP conformation. Our results revealed that nonconserved region of {sigma} is an allosteric controller of transcription initiation and demonstrated how basal transcription factors can regulate gene expression by modulating the RNAP holoenzyme assembly and hibernation.

molecular biology↗

bioRxiv2022

The N-terminal domain of MX1 proteins is essential for their antiviral activity against different families of RNA viruses

Myxovirus resistance protein 1 (MX1) and MX2, are homologous, dynamin-like large GTPases, induced upon interferon (IFN) exposure. Human MX1 (HsMX1) is known to inhibit many viruses, including influenza A virus (IAV), by likely acting at various steps of their life cycles. Despite decades of studies, the mechanism(s) of action with which MX1 proteins manage to inhibit target viruses is not fully understood. MX1 proteins are mechano-enzymes and share a similar organization to dynamin, with an amino-terminal GTPase domain and a carboxy-terminal stalk domain, connected by a Bundle Signalling Element (BSE). These three elements are known to be essential for antiviral activity. HsMX1 has two unstructured regions, the L4 loop, also essential for antiviral activity, and a short amino (N)-terminal region, which greatly varies between MX1 proteins of different species. The role of this N-terminal domain in antiviral activity is not known. Herein, using mutagenesis, imaging and biochemical approaches, we demonstrate that the N-terminal domain of HsMX1 is essential for antiviral activity against IAV and Vesicular Stomatitis Virus (VSV), and for the ability to aggregate Orthobunyavirus nucleoproteins. Furthermore, we pinpoint a highly conserved leucine within this region, which is absolutely crucial for human, mouse and bat MX1 protein antiviral activity. Importantly, mutation of this leucine does not compromise GTPase activity or oligomerization capabilities, but does modify MX1 protein subcellular localisation. The discovery of this essential and highly conserved residue defines this region as key and may reveal insights as to the mechanism of action of MX1 proteins.

microbiology↗

bioRxiv2018

Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites.

Metabolic alterations support cellular transformation. Noticeably, cellular transformation and cancer progression is associated with accumulation of dihydrouracil and dihydrothymine. However, it remains elusive how dihydropyrimidine metabolites affect cellular phenotypes. Dihydropyrimidines are degraded by dihydropyrimidinase (DHP). This zinc metalloenzyme is upregulated in solid tumors but not in the corresponding normal tissues. Here we show that DHP silencing in transformed cell lines is cytotoxic. Increasing the level of dihydropyrimidines inhibited DNA replication and transcription. It induced replication stress signaling by ATR and p53 stabilization. Remarkably, cells lacking DHP accumulated DNA-protein crosslinks (DPCs). Among DPCs, covalently trapped translesion DNA polymerase {eta} contributed to the cytotoxicity of dihydropyrimidines. Furthermore, we show that the plant flavonoid dihydromyricetin inhibits the activity of recombinant human DHP. Cellular treatment with dihydromyricetin triggered DPCs-dependent DNA replication stress. This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of DHP activity in solid tumors.

cancer biology↗