2 years Postdoctoral fellowship at Inserm U1236 (University of Rennes, France)
Caveolin Expressions & Functions in Activated B Cells and Plasma Cells
B cells are the main cells of the adaptive immune response being able to give rise to antibodyproducing effector cells, plasma cells (PC), or to memory B cells. Understanding the B cell differentiation into PC is essential because this complex process, which involves a great diversity of tissues (blood, spleen, bone marrow), induces deep cellular modifications including vast internal membranes reorganizations necessary for the acquisition of immunoglobulin (Ig) secretion. Thanks to transcriptomic and functional experiments, we identified CAV1, the gene encoding Caveolin1 protein (Cav1), as one of the first genes induced in PC progenitors after B cell activation, this expression being maintained in mature PCs. After siRNA blocking of CAV1 expression, cells showed several modifiedfunctions, including Ig secretion, PC responses to TGFβ and cell response to the endoplasmic reticulum stress and autophagy. Cav1 is known as a mandatory constituent of caveolae, invaginations of the plasma membrane characterized by their capacity to impact cell response to mechanical constraints. Our preliminary analyzes on PC progenitors revealed two unusual facts: 1) expression of the rarer and under-studiedCav1-beta isoform, and 2) a lack of expression of other proteins constitutive of caveolae. These results signify a peculiar situation for Cav1 in the B cell lineage and prompted us to address a provocative hypothesis that this protein would act in internal membranes via a free form, forming clusters that could disassemble after mechanical stress. This project gives the opportunity to join two complementary expertise, B cell immunology (U1236) and cell biology (U1143), to explore new cellular mechanisms driven by Cav1 in the context of B cell differentiation, PC development and PC identity maintenance. We will focus our work on human B cells and primary cell cultures as well as PC cell lines. Several tools have been developed to modulate the expression of selected genes, which makes it possible to dissect various steps characterizing B cell commitment in PC.
Three main objectives will be followed: 1) To characterize the regulation of CAV1 gene expression during the B cell differentiation, the goal is to decipher the connection between the transcriptional cascade governing the step-wise differentiation process and the emergence/maintenance of CAV1 expression in cells that initially lack its expression; 2) To study the role of non-caveolar Cav1 protein in internal membranes dynamics and cell signaling, with a special interest for the JAK / STAT and TGFβ / BMP signaling; 3) To explore the role of Cav1 in Igs secretion, autophagy, UPR response and cell survival, all these functions being required for PC long-term maintenance.
The post-doctoral fellow will be fully in charge of the first objective, largely implicated in the second and partially in the third.
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