A5084591075- Drug Transport and Resistance Mechanisms
- T-cell and B-cell Immunology
- Protein Kinase Regulation and GTPase Signaling
- Cellular transport and secretion
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- Liver Disease Diagnosis and Treatment
- Drug-Induced Hepatotoxicity and Protection
- Estrogen and related hormone effects
- CAR-T cell therapy research
- Pharmacological Effects and Toxicity Studies
- Glycosylation and Glycoproteins Research
- Calcium signaling and nucleotide metabolism
- Ubiquitin and proteasome pathways
- Pediatric Hepatobiliary Diseases and Treatments
- Cell Adhesion Molecules Research
- Receptor Mechanisms and Signaling
- Extracellular vesicles in disease
- Neonatal Health and Biochemistry
- Cellular Mechanics and Interactions
- Liver physiology and pathology
- RNA Research and Splicing
- Fibroblast Growth Factor Research
- Pharmacogenetics and Drug Metabolism
- Genetic and Kidney Cyst Diseases
HiFiBiO Therapeutics (France)
2024
Inserm
2017-2023
Institut Curie
2017-2023
Université Paris Sciences et Lettres
2017-2023
Immunité et Cancer
2020
National University of Rosario
2008-2019
Consejo Nacional de Investigaciones Científicas y Técnicas
2009-2019
Universitat de València
2012
Instituto de Fisiología Vegetal
2010
The adapter molecule linker for activation of T cells (LAT) orchestrates the formation signalosomes upon cell receptor (TCR) stimulation. LAT is present in different intracellular pools and dynamically recruited to immune synapse However, traffic its function lymphocyte are ill defined. We show herein that LAT, once internalized, transits through Golgi–trans-Golgi network (TGN), where it repolarized synapse. This retrograde transport depends on small GTPase Rab6 target soluble...
Abstract The endogenous estradiol metabolite 17β-d-glucuronide (E217G) induces an acute cholestasis in rat liver coincident with retrieval of the canalicular transporters bile salt export pump (Bsep, Abcc11) and multidrug resistance-associated protein 2 (Mrp2, Abcc2) their associated loss function. We assessed participation Ca2+-dependent kinase C isoforms (cPKC) cholestatic manifestations E217G perfused (PRL) isolated hepatocyte couplets (IRHCs). In PRL, (2 μmol/liver; intraportal, single...
Estradiol 17β-D-glucuronide (E217G) is an endogenous, cholestatic metabolite that induces endocytic internalization of the canalicular transporters relevant to bile secretion: salt export pump (Bsep) and multidrug resistance–associated protein 2 (Mrp2). We assessed whether phosphoinositide 3-kinase (PI3K) involved in E217G-induced cholestasis. E217G activated PI3K according assessment phosphorylation final effector, kinase B (Akt). When inhibitor wortmannin (WM) was preadministered isolated...
Estradiol-17ß-D-glucuronide (E17G) activates different signaling pathways (e.g., Ca(2+) -dependent protein kinase C, phosphoinositide 3-kinase/protein B, mitogen-activated kinases [MAPKs] p38 and extracellular signal-related 1/2, estrogen receptor alpha) that lead to acute cholestasis in rat liver with retrieval of the canalicular transporters, bile salt export pump (Abcb11) multidrug resistance-associated 2 (Abcc2). E17G shares nonconjugated estradiol capacity activate these pathways....
T cell receptor (TCR) activation is modulated by mechanisms such as TCR endocytosis, which thought to terminate signalling. Here we show that, upon internalization, continues signal from a set of specialized endosomes that are crucial for functions. Mechanistically, ligation leads clathrin-mediated internalization the TCR-CD3ζ complex, while maintaining CD3ζ signalling, in endosomal vesicles contain insulin responsive aminopeptidase (IRAP) and SNARE protein Syntaxin 6. Destabilization this...
Abstract Background: Infiltrating regulatory T cells (Tregs) are part of the tolerogenic microenvironment tumors and key players in resistance to immune checkpoint inhibitor (ICI) therapy. Selective depletion Tregs within tumor has potential overcome this increase proportion patients responding immunotherapy. The CCR8 chemokine receptor, which is preferentially upregulated on tumor-resident Tregs, represents an attractive specific target for antibody-dependent cell cytotoxicity...
Abstract The T cell immune synapse is a site of intense vesicular trafficking. Here we show that the golgin GMAP210, known to capture vesicles and organize membrane traffic at Golgi, involved in transport LAT synapse. Upon activation, more GMAP210 interact with LAT-containing go together Regulating recruitment LAT-dependent signaling, controls activation. Using rerouting assay, captures VAMP7-decorated vesicles. Overexpressing different domains also allows their specific delivery by...
Abstract Palmitoylation is the reversible addition of palmitate to cysteine via a thioester linkage. The nature this modification makes it prime candidate as mechanism for regulating signal transduction in T-cell receptor signaling. Following stimulation we find number proteins are newly palmitoylated, including those involved vesicle-mediated transport and Ras transduction. Among these stimulation-dependent palmitoylation targets v-SNARE VAMP7, important docking vesicular LAT during TCR...
Objective The endogenous, cholestatic metabolite estradiol 17ß-d-glucuronide (E217G) induces endocytic internalization of the canalicular transporters relevant to bile formation, Bsep and Mrp2. We evaluated here whether MAPKs are involved in this effect. Design ERK1/2, JNK1/2, p38 MAPK activation was assessed by increase their phosphorylation status. Hepatocanalicular function isolated rat hepatocyte couplets (IRHCs) quantifying apical secretion fluorescent Mrp2 substrates, isolated,...
In estradiol 17β-d-glucuronide (E17G)-induced cholestasis, the canalicular hepatocellular transporters bile salt export pump (Abcb11) and multidrug-resistance associated protein 2 (Abcc2) undergo endocytic internalization. cAMP stimulates trafficking of transporter-containing vesicles to apical membrane is able prevent internalization these in estrogen-induced cholestasis. Hepatocyte levels are regulated by hormones such as glucagon adrenaline (via β2 receptor). We analyzed effects...
Estradiol 17ß-d-glucuronide (E17G) induces acute cholestasis in rat with endocytic internalization of the canalicular transporters bile salt export pump (Abcb11) and multidrug resistance-associated protein 2 (Abcc2). Classical kinase C (cPKC) PI3K pathways play complementary roles E17G cholestasis. Since non-conjugated estradiol is capable activating these via estrogen receptor alpha (ERα), we assessed participation this cholestatic manifestations glucuronidated-metabolite perfused liver...
Engagement of the receptor programmed cell death molecule 1 (PD-1) by its ligands PD-L1 and PD-L2 inhibits T cell–mediated immune responses. Blocking such signaling provides clinical effects PD-1–targeted immunotherapy. Here, we investigated mechanisms underlying PD-1–mediated inhibition. Because dynamic actin remodeling is crucial for functions, characterized PD-1 engagement on at immunological synapse, interface between a an antigen-presenting (APC) or target cell. We used microscopy to...
We have previously observed that in response to antigenic activation, T cells produce actin-rich protrusions generate forces involved cell activation. These are influenced by the mechanical properties of antigen-presenting (APCs). However, how external forces, which can be produced APCs, influence dynamic actin protrusion remains unknown. In this study, we quantitatively characterised effects grown activated cells.Using a micropipette force probe, applied controlled compressive or pulling on...
LAT is an important player of the signaling cascade induced by TCR activation. This adapter molecule present at plasma membrane T lymphocytes and more abundantly in intracellular compartments. Upon cell activation pool recruited to immune synapse (IS). We previously described two pathways controlling trafficking: retrograde transport from endosomes TGN, anterograde traffic Golgi IS. address specific role four proteins, GTPase Rab6, t-SNARE syntaxin-16, v-SNARE VAMP7 golgin GMAP210, each...
Abstract Introduction Immune checkpoint blockade (ICB) therapies targeting PD-1/PD-L1 or CTLA-4 have greatly improved clinical outcome in many cancers. However, multiple mechanisms of resistance to ICB severely limit the number patients experiencing long-term survival benefits. Overcoming represents a significant challenge for drug development. Regulatory T cells (Tregs) tumor microenvironment (TME) prevent effector (Teffs) from mounting productive immune response and been implicated...
In obstructive cholestasis, there is an integral adaptive response aimed to diminish the bile flow and minimize injury of ducts caused by increased intraluminal pressure harmful levels salts bilirrubin. Canalicular bicarbonate secretion, driven anion exchanger 2 (AE2), influential determinant canalicular salt-independent flow. this work, we ascertained whether AE2 expression and/or activity reduced in hepatocytes from rats with common duct ligation (BDL), as part cholestasis. After 4 days...