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|Title:||Characterisation of the voltage gated proton channel HVCN1 in B cells|
|Authors:||Bhamrah, Mandeep Kaur|
|Presented at:||University of Leicester|
|Abstract:||HVCN1 is a voltage-gated proton channel, detected in a proteomic screen profiling membrane proteins of Mantle Cell Lymphoma cells. Subsequent analysis showed that HVCN1 is expressed in naive mature resting B cells, such as cells of Mantle Zones in lymph nodes and circulating peripheral B cells. The role of voltage-proton channels in B cells is unknown and further characterized in this study. HVCN1 co-localizes with the BCR and markers of MIIC vesicles and translocates with the BCR upon internalization of receptor-antigen complexes. Mass spectrometry data confirmed key proteins involved in BCR signalling, such as IgM, CD79B (Igp), CD19 and CD22 were associated with HVCN1 at a resting and stimulated state of the cell, demonstrating HVCN1 functioned in the regulation of B-cell receptor signalling. BCR stimulation has shown to result in the production of ROS, which can regulate B-cell activation, through the oxidation of Protein Tyrosine Phosphatases. Primary B cells isolated from mice lacking HVCN1 demonstrated weak signalling following cross-linking of the BCR with anti-IgM, which was rescued in the presence of the Sodium Stibogluconate, an inhibitor of the CD22 associated phosphatase SHP-1. The catalytic activity of phosphatases was reduced by ROS and allowed phosphorylation of protein, which was regulated through a negative signalling feedback loop. Lack of HVCN1 dampened the phosphorylation of key signalling molecules SYK and AKT, involved in the activation and proliferation of B cells. Therefore, HVCN1 functions to modulate the balance of ROS production in the cell upon BCR activation, allowing the effective transmission of signalling in the cell.|
|Rights:||Copyright © the author. All rights reserved.|
|Appears in Collections:||Theses, Dept. of Cancer Studies & Molecular Medicine|
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