Proteogenomic Identification of Membrane Trafficking Components affecting Antibody Secretion in Plasma Cells

Plasma cells are professional antibody secreting cells unlike their naïve B cell (NBC) precursors. By exploiting the remarkable contrast in their secretory capacity, we set out to identify novel factors involved in antibody secretion and PC physiology using a multiplatform, cross-species proteogenomics approach. Using this methodology, we have reproducibly identified a large number of genes which were consistently upregulated in antibody secreting cells (ASCs). As expected, genes involved in protein folding and membrane trafficking are significantly enriched in our data set thus validating this method. As thousands of genes were differentially regulated in PCs, we generated a web based bioresource to aid in the visualisation of our data. Using this resource, we have investigated the regulation of several genes families during plasma cell differentiation including transcription factors, coat proteins, tethers and SNAREs. Our analysis suggests that ASCs specifically upregulate vesicle coats and tethers acting in the early but not the late secretory pathway. Interestingly, several genes implicated in collagen secretion are also significantly upregulated in ASCs suggesting that they may have a more general role in secretion than previously thought. For example, we have identified that NBAS a component of the ER localised tethering complex is upregulated in ASC which may explain why patients with mutations in this gene have defects in collagen secretion and hypogammaglobulinemia. Using the web-based resource, we have also identified a large number of poorly characterised genes which are significantly upregulated in ASCs so potentially having a role in antibody folding and/or trafficking (CRELD2, TMEM214 and HID1). Finally, this web-based resource will be useful for those aiming to identify novel biomarkers for plasma cells and factors which can be manipulated to enhance secretory capacity.