Exploration des mécanismes responsables de la dichotomie entre la chimiotaxie et la division cellulaire

La division cellulaire (mitose) et la migration cellulaire dirigée vers un gradient de chimioattractants (chimiotaxie) sont deux processus fondamentaux en biologie cellulaire qui impliquent tous les deux la polarisation de la cellule. Dans la mitose, la polarisation de la cellule est bipolaire, définissant des pôles opposés de la cellule vers lesquels les chromosomes et le contenu cellulaire des futures cellules filles en division sont attirés. En revanche, la chimiotaxie nécessite une polarisation unipolaire, définissant un pôle dirigeant (avant) et une queue traînante (arrière). Ces modes de polarisation différents sont fondamentalement incompatibles. Il est donc intuitivement évident qu’une cellule en division aiguë ne peut pas simultanément déclencher un mécanisme de polarisation contradictoire, mais qu’elle doit rester insensible aux signaux chimiotactiques. Étonnamment, la démonstration d’une dichotomie entre mitose et chimiotaxie n’avait pas été faite. De plus, on ignore quand et comment une cellule en division devient insensible aux signaux chimiotactiques. Dans cette étude, nous démontrons l’existence de la dichotomie entre la chimiotaxie et les phases du cycle cellulaire dont le mode de polarisation est bipolaire, soit la fin de la phase G2 et M dans un modèle humain, les cellules souches pré-B. Nous démontrons que ceci n’est pas dû à une réduction d’expression du récepteur chimioattractant en surface des cellules en phases G2 et M; de plus, la signalisation proximale du récepteur semble intacte. D’autres mécanismes qu’une régulation négative du récepteur chimioattractant lors des phases G2 et M doivent alors être envisagés.Cell division (mitosis) and directed cell migration towards chemoattractants (chemotaxis) are two central processes in cell biology that both involve cell polarization. In mitosis, cell polarization is bipolar, defining opposite poles on the cell towards which chromosomes and cellular content of the eventually separating daughter cells are attracted. In contrast, chemotaxis ascending a concentration gradient of exogenous chemoattractants requires unipolar polarization, defining a leading edge (front) and a trailing end (rear). These different polarization patterns are fundamentally incompatible. It is thus intuitively obvious that an acutely dividing cell cannot simultaneously set off a conflicting polarization program, but must remain unresponsive to chemotactic cues. Surprisingly, no demonstration of the chemotaxis-mitosis dichotomy has been published. Furthermore, it remains unknown when, and how, a dividing cells become unresponsive to chemotactic cues. In this study, we demonstrate the existence of the dichotomy between chemotaxis and mitosis in pre-B human cells. More specifically, we demonstrate that the dichotomy is not a cause of the reduction of cell surface expression of chemokine receptor during the cell synchronisation at the G2 and M phases’s border. We also prove that cells undergoing bipolarization at the G2 and M border still keep their proximal chemokine receptor-dependant signaling pathways. Other mechanisms than a negative regulation of the chemokine receptor must be investigated

Pharmacogenomics of the efficacy and safety of Colchicine in COLCOT

© 2021 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.Background: The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine. Methods: There were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients. Results: None of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52-2.35], P=7.41×10-9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82-3.47]; P=2.70×10-8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant. Conclusions: We found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.info:eu-repo/semantics/publishedVersio

Receptor Complementation and Mutagenesis Reveal SR-BI as an Essential HCV Entry Factor and Functionally Imply Its Intra- and Extra-Cellular Domains

HCV entry into cells is a multi-step and slow process. It is believed that the initial capture of HCV particles by glycosaminoglycans and/or lipoprotein receptors is followed by coordinated interactions with the scavenger receptor class B type I (SR-BI), a major receptor of high-density lipoprotein (HDL), the CD81 tetraspanin, and the tight junction protein Claudin-1, ultimately leading to uptake and cellular penetration of HCV via low-pH endosomes. Several reports have indicated that HDL promotes HCV entry through interaction with SR-BI. This pathway remains largely elusive, although it was shown that HDL neither associates with HCV particles nor modulates HCV binding to SR-BI. In contrast to CD81 and Claudin-1, the importance of SR-BI has only been addressed indirectly because of lack of cells in which functional complementation assays with mutant receptors could be performed. Here we identified for the first time two cell types that supported HCVpp and HCVcc entry upon ectopic SR-BI expression. Remarkably, the undetectable expression of SR-BI in rat hepatoma cells allowed unambiguous investigation of human SR-BI functions during HCV entry. By expressing different SR-BI mutants in either cell line, our results revealed features of SR-BI intracellular domains that influence HCV infectivity without affecting receptor binding and stimulation of HCV entry induced by HDL/SR-BI interaction. Conversely, we identified positions of SR-BI ectodomain that, by altering HCV binding, inhibit entry. Finally, we characterized alternative ectodomain determinants that, by reducing SR-BI cholesterol uptake and efflux functions, abolish HDL-mediated infection-enhancement. Altogether, we demonstrate that SR-BI is an essential HCV entry factor. Moreover, our results highlight specific SR-BI determinants required during HCV entry and physiological lipid transfer functions hijacked by HCV to favor infection