Biology subjects

Chatel-Chaix, L.

Publications and source records attributed to Chatel-Chaix, L..

5 recordsLinked to original sources

bioRxiv2025

A genus-wide interaction atlas across NS4B orthologues identifies a conserved role for UFMylation in orthoflavivirus replication

Orthoflavivirus infections represent an increasing public health burden, with several members of the genus emerging or re-emerging globally. Despite the availability of few vaccines, no antiviral drugs are currently licensed for the treatment of orthoflavivirus infections. Several pre-clinical studies identified the non-structural protein 4B (NS4B), one of the least characterized viral proteins within the orthoflavivirus genus, as the most promising target for the development of potent direct-acting antivirals. However, its functional roles in viral replication are still elusive. Here, we employ an integrated proteomic approach to systematically identify cellular targets of NS4B across eight prototypic orthoflaviviruses and characterize their influence on the human proteome. Using this approach, we mapped high-confidence NS4B-interacting human proteins across the genus, underlying potentially divergent mechanisms of host adaptation across orthoflaviviruses spanning diverse pathologies and vector preferences. Among these, we unveil a novel function for UBA5, the E1-activating enzyme of the UFMylation pathway, in orthoflavivirus replication. Mechanistically, we map associations of distinct viral proteins with multiple members of the UFMylation pathway, which are selectively recruited to sites of viral replication to promote mitochondrial respiration. Finally, we demonstrate that pharmacological inhibition of UFMylation exerts potent antiviral activity in vitro and in vivo. This integrative study provides a rational framework for a system-level understanding of orthoflavivirus NS4B effector functions and sheds light on a conserved and unconventional role for UFMylation in orthoflavivirus replication.

microbiology↗

bioRxiv2024

A novel in vivo model of Zika virus infection unveils NS4A as a key determinant of neuropathogenesis

Infection of pregnant women by Zika virus (ZIKV) is associated with severe neurodevelopmental defects in newborns through poorly defined mechanisms. Here, we engineered a zebrafish in vivo model of ZIKV infection to circumvent limitations of existing mammalian models. Leveraging the unique tractability of this system, we gained unprecedented access to the ZIKV-infected brain at early developmental stages. The infection of zebrafish larvae with ZIKV phenocopied the disease in mammals including a reduced head area and neural progenitor cells (NPC) infection and depletion. Moreover, transcriptomic analyses of ZIKV-infected NPCs revealed a distinct dysregulation of genes involved in survival and neuronal differentiation, including downregulation of the expression of the glutamate transporter vglut1, resulting in an altered glutamatergic network in the brain. Mechanistically, ectopic expression of ZIKV protein NS4A in the larvae recapitulated the morphological defects observed in infected animals, identifying NS4A as a key determinant of neurovirulence and a promising antiviral target for developing therapies.

microbiology↗

bioRxiv2024

Extracellular matrix signals promotes actin-dependent mitochondrial elongation and activity

Mitochondria are crucial metabolic organelles that are regulated by both intracellular and extracellular cues. The extracellular matrix (ECM) is a key component of the cellular environment that controls cellular behavior and metabolic activity. Here, we determined how ECM signalling regulates mitochondrial structure and activity. To distinguish mitochondrial regulation from the general survival cues generated by the ECM, we used breast cancer-derived spheres (mammospheres) because of their ability to grow in suspension culture in the absence of ECM. Using this system, we demonstrate that the association of mammospheres with the ECM results in dramatic mitochondrial elongation, along with enhanced mitochondrial respiration and ATP production. This remodeling occurs independently of DRP1 activity, but relies on integrin signaling and actin polymerization. Therefore, our findings demonstrate that ECM-driven actin polymerization plays a crucial role in remodeling mitochondrial networks to promote OXPHOS, which represents a vital step for migrating cells to enhance cellular adhesion and facilitate cell growth.

cell biology↗

bioRxiv2023

Zika virus remodels and hijacks IGF2BP2 ribonucleoprotein complex to promote viral replication organelle biogenesis

Zika virus (ZIKV) infection causes significant human disease that, with no approved treatment or vaccine, constitutes a major public health concern. Its life cycle entirely relies on the cytoplasmic fate of the viral RNA genome (vRNA) through a fine-tuned equilibrium between vRNA translation, replication and packaging into new virions, all within virus-induced replication organelles (vRO). In this study, with an RNAi mini-screening and subsequent functional characterization, we have identified insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) as a new host dependency factor that regulates vRNA synthesis. In infected cells, IGF2BP2 associates with viral NS5 polymerase and redistributes to the perinuclear viral replication compartment. Combined fluorescence in situ hybridization-based confocal imaging, in vitro binding assays, and immunoprecipitation coupled to RT-qPCR, showed that IGF2BP2 directly interacts with ZIKV vRNA 3-nontranslated region. Using ZIKV sub-genomic replicons and a replication-independent vRO induction system, we demonstrated that IGF2BP2 knockdown impairs de novo viral organelle biogenesis and, consistently, vRNA synthesis. Finally, the analysis of immunopurified IGF2BP2 complex using quantitative mass spectrometry and RT-qPCR, revealed that ZIKV infection alters the protein and RNA interactomes of IGF2BP2. Altogether, our data support that ZIKV hijacks and remodels the IGF2BP2 ribonucleoprotein complex to regulate vRO biogenesis and vRNA neosynthesis.

microbiology↗

bioRxiv2023

Flaviviruses alter endoplasmic reticulum-mitochondria contacts to regulate respiration and apoptosis

With no therapeutics available, there is an urgent need to better understand the pathogenesis of flaviviruses which constitute a threat to public health worldwide. During infection, dengue virus (DENV) and Zika virus (ZIKV), two flaviviruses induce alterations of mitochondria morphology to favor viral replication, suggesting a viral co-opting of mitochondria functions. Here, we performed an extensive transmission electron microscopy-based quantitative analysis to demonstrate that both DENV and ZIKV alter endoplasmic reticulum-mitochondria contacts (ERMC). This correlated at the molecular level with an impairment of ERMC tethering protein complexes located at the surface of both organelles. Furthermore, virus infection, as well as NS4B expression modulated the mitochondrial oxygen consumption rate. Consistently, metabolomic and mitoproteomic analyses revealed a decrease in the abundance of several metabolites of the Krebs cycle and changes in the stoichiometry of the electron transport chain. Most importantly, ERMC destabilization by protein knockdown increased virus replication while dampening ZIKV-induced apoptosis. Overall, our results support the notion that flaviviruses hijack ERMCs to generate a cytoplasmic environment beneficial for sustained and efficient replication.

microbiology↗