Biology subjects

Mignen, O.

Publications and source records attributed to Mignen, O..

4 recordsLinked to original sources

bioRxiv2026

STIM1 at the plasma membrane: A novel Molecular regulator of B cell migration.

Cell migration is a fundamental process required for effective immune responses, relying on both amoeboid movement and chemotaxis. Among chemotactic pathways, the CXCL12/CXCR4 axis plays a pivotal role in guiding B cell migration. While essential under physiological conditions, this pathway is frequently dysregulated in pathological contexts such as Chronic Lymphocytic Leukemia (CLL) and Systemic Lupus Erythematosus (SLE), where altered CXCR4 expression enhances B cell retention, survival, and tissue infiltration. Calcium signaling is central to B cell migration, notably through Store-Operated Calcium Entry (SOCE), STIM1 located at the endoplasmic reticulum (ER) membrane and Orai1 calcium channels. Although STIM1 is traditionally studied as an ER protein regulating SOCE, early findings and recent work from our group indicate that STIM1 is also present at the plasma membrane (STIM1PM), where it displays a dual topology and contributes to constitutive calcium entry (CCE). The function of STIM1PM pool in B cell migration remains unknown. Here, we demonstrate that both STIM1ER and Orai1 are required for CXCL12-induced migration of B cells. Importantly, we provide the first evidence that STIM1PM, exhibiting N?terminal and C?terminal orientations, actively regulates B cell migration independently of SOCE. We show that STIM1PM controls CCE and modulates intercellular interactions, thereby influencing chemotactic responses. Targeting STIM1PM domains significantly impairs B cell migration, highlighting its potential as a novel therapeutic target in diseases characterized by aberrant B cell trafficking. Our findings uncover an unanticipated role for STIM1PM and open new perspectives on calcium?dependent and calcium?independent mechanisms of B cell migration.

cell biology↗

bioRxiv2023

Blocking Orai1 constitutive activity inhibits B-cell cancer migration and synergistically acts with drugs to reduce B-CLL cell survival

Orai1 channel capacity to control store-operated Ca2+ entry (SOCE) and B-cell functions is poorly understood and more specifically in B-cell cancers, including human lymphoma and leukemia. As compared to normal B-cells, Orai1 is overexpressed in B-chronic lymphocytic leukemia (B-CLL) and contributes in resting B-CLL to mediate an elevated basal Ca2+ level through a constitutive Ca2+ entry, and in BCR-activated B-cell to regulate the Ca2+ signaling response. Such observations were confirmed in human B-cell lymphoma and leukemia lines, including RAMOS, JOK-1, MEC-1 and JVM-3 cells. Next, the use of pharmacological Orai1 inhibitors (GSK-7975A and Synta66) blocks constitutive Ca2+ entry and in turn affects B-cell cancer (primary and cell lines) survival and migration, controls cell cycle, and induces apoptosis through a mitochondrial and caspase-3 independent pathway. Finally, the added value of Orai1 inhibitors in combination with B-CLL drugs (ibrutinib, idelalisib, rituximab, and venetoclax) on B-CLL survival was tested, showing an additive/synergistic effect including in the B-cell cancer lines. To conclude, this study highlights the pathophysiological role of the Ca2+ channel Orai1 in B-cell cancers, and pave the way for the use of ORAI1 modulators as a plausible therapeutic strategy.

cancer biology↗

bioRxiv2021

IL-21 and IFN-α have both opposite and redundant role on human innate precursors and memory B-cell differentiation.

Immunological memory is essential for effective immune protection upon antigen rechallenge. Memory B cells encompass multiple subsets, heterogeneous in terms of phenotypes, origins and precursors, anatomical localization, and functional responses. B-cell responses are conditioned by micro-environmental signals, including cytokines. Here, we analyzed in vitro the effects of two cytokines implicated in B-cell differentiation, interferon-alpha (IFN-) and interleukin (IL)-21, on the early functional response of four different mature B-cell subsets (IgD- CD27- naive, IgD+ CD27+ unswitched, IgD- CD27+ switched and double-negative B cells). The dual response of naive and memory B cells to IL-21 allowed us to uncover a unique IgD+ CD27- CD10- B-cell population (referred to as NARB+) characterized by the expression of marginal zone B-cell markers CD45RB and CD1c. Similar to memory B cells, NARB+ cells were in a pre-activated state, allowing them to rapidly differentiate into plasmablasts upon innate signals while maintaining their susceptibility to IL-21 activation-induced apoptosis as observed for the naive compartment. Both in-depth phenotypic analysis of circulating B cells, and identification of these cells in spleen, tonsil and gut-associated lymphoid tissues, supported that NARB+ are uncommitted precursors of human marginal zone B cells.

immunology↗

bioRxiv2020

p.E152K-STIM1 mutation deregulates Ca2+ signaling contributing to chronic pancreatitis.

Since deregulation of intracellular Ca2+ can lead to intracellular trypsin activation and STIM1 (stromal interaction molecule-1) protein is the main regulator of Ca2+ homeostasis in pancreatic acinar cells, we explored the Ca2+ signaling in 37 STIM1 variants found in three pancreatitis patient cohorts. Extensive functional analysis of one particular variant, p.E152K, identified in three patients, provided a plausible link between dysregulated Ca2+ signaling within pancreatic acinar cells and chronic pancreatitis susceptibility. Specifically, p.E152K, located within the STIM1 EF-hand and sterile -motif domain, increased the release of Ca2+ from the endoplasmic reticulum in patient-derived fibroblasts and transfected HEK293T cells. This event was mediated by altered STIM1-sarco/endoplasmic reticulum calcium transport ATPase (SERCA) interactions and enhanced SERCA pump activity leading to increased Store Operated Calcium Entry (SOCE). In the pancreatic AR42J cells expressing the p.E152K variant, Ca2+-signaling perturbations correlated with defects in trypsin activation and secretion, and increased cytotoxicity after cholecystokinin stimulation. Summary statementp.E152K-STIM1 variant found in pancreatitis patients leads to intracellular changes in calcium homeostasis through SERCA interaction, enabling intracellular trypsin activation and pancreatic acinar cell death.

cell biology↗