Biology subjects

Musnier, A.

Publications and source records attributed to Musnier, A..

3 recordsLinked to original sources

bioRxiv2024

Hormone-regulated dynamics of mRNA distribution on ribosomes in Sertoli cells

The effects of hormone stimulation on the cell translational profile remain poorly understood. Here, using polysome profiling combined to RNA sequencing, we analyzed the translational response to follicle-stimulating hormone (FSH) of primary rat Sertoli cells, that exhibit an active anabolic activity regulated by reproductive hormones in the male gonad. We first established that mRNA distribution to polysomes follows a bimodal pattern, with 15% of mRNAs enriched in polysomes and exhibiting high expression. Critically, this basal polysomal enrichment had a major impact on FSH-induced mRNA recruitment to the polysomes, since FSH stimulation promoted the release of polysome-enriched mRNAs, while mRNAs that were the least associated to polysomes were preferentially recruited to polysomes upon stimulation. The FSH signal did not alter the core biological functions of Sertoli cells, but shifted the proteins involved in these functions, suggesting a molecular rewiring of the FSH-induced gene expression. These findings underscore how ribosomal reallocation dynamically adapts the cellular translatome to microenvironmental changes, enabling cells to fine-tune protein production in response to external stimuli. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/629416v1_ufig1.gif" ALT="Figure 1000"> View larger version (19K): org.highwire.dtl.DTLVardef@27334forg.highwire.dtl.DTLVardef@199c630org.highwire.dtl.DTLVardef@a28b92org.highwire.dtl.DTLVardef@1794172_HPS_FORMAT_FIGEXP M_FIG C_FIG Bullet points* In Sertoli cells, most mRNAs distribute similarly between monosomes and polysomes, but a sub-population is specifically enriched in polysomes * Basal polysomal enrichment level has a major impact on FSH-induced mRNA recruitment or release from the polysomes * The FSH signal induced a global rewiring of the proteins involved in Sertoli cell basal activity * FSH-induced reassignment of ribosomes to specific mRNAs has to comply with a tightly maintained mRNA distribution landscape

systems biology↗

bioRxiv2020

Exploring epitope and functional diversity of anti-SARS-CoV2 antibodies using AI-based methods

Since the beginning of the COVID19 pandemics, an unprecedented research effort has been conducted to analyze the antibody responses in patients, and many trials based on passive immunotherapy -- notably monoclonal antibodies -- are ongoing. Twenty-one antibodies have entered clinical trials, 6 having reached phase 2/3, phase 3 or having received emergency authorization. These represent only the tip of the iceberg, since many more antibodies have been discovered and represent opportunities either for diagnosis purposes or as drug candidates. The main problem facing laboratories willing to develop such antibodies is the huge task of analyzing them and choosing the best candidate for exhaustive experimental validation. In this work we show how artificial intelligence-based methods can help in analyzing large sets of antibodies in order to determine in a few hours the best candidates in few hours. The MAbCluster method, which only requires knowledge of the amino acid sequences of the antibodies, allows to group the antibodies having the same epitope, considering only their amino acid sequences and their 3D structures (actual or predicted), and to infer some of their functional properties. We then use MAbTope to predict the epitopes for all antibodies for which they are not already known. This allows an exhaustive comparison of the available epitopes, but also gives a synthetic view of the possible combinations. Finally, we show how these results can be used to predict which antibodies might be affected by the different mutations arising in the circulating strains of the virus, such as the N501Y mutation that has started to spread in Great-Britain.

bioinformatics↗

bioRxiv2019

Biasing HER4 Tyrosine Kinase Signaling with Antibodies: Induction of Cell Death by Antibody-Dependent HER4 Intracellular Domain Trafficking

HER4 isoforms have oncogenic or tumor suppressor functions depending on their susceptibility to proteolytic cleavage and HER4 Intracellular Domain (4ICD) translocation. Here, we report that the NRG1 tumor suppressor mechanism through the HER4 JMa/CYT1 isoform can be mimicked by the agonist anti-HER4 antibody C6. NRG1 induced cleavage of poly(ADP-ribose) polymerase (PARP) and sub-G1 DNA fragmentation, and also reduced the metabolic activity of HER3-negative/HER4-positive cervical (C-33A) and ovarian (COV318) cancer cells. This effect was confirmed in HER4 JMa/CYT1-, but not JMa/CYT2-transfected BT549 triple-negative breast cancer cells. NRG1 favored 4ICD cleavage and retention in mitochondria in JMa/CYT1-transfected BT549 cells, leading to Reactive Oxygen Species (ROS) production through mitochondrial depolarization. Similarly, the anti-HER4 antibody C6, which binds to a conformational epitope located on aa 575-592 and 605-620 of HER4 domain IV, induced 4ICD cleavage and retention in mitochondria, and mimicked NRG1-mediated effects on PARP cleavage, ROS production, and mitochondrial membrane depolarization in cancer cells. In vivo, C6 reduced growth of COV434 and HCC187 tumor cell xenografts in nude mice. Biasing 4ICD trafficking to mitochondria with anti-HER4 antibodies to mimic NRG1 suppressor functions could be an alternative anti-cancer strategy.

cancer biology↗