Regulation of antibody secreting cell (ASC) homeostasis by Ufbp1.

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Secreted antibodies play an important role in the neutralization of pathogens and the protection of host. Two types of ASCs develop during B cell responses: short lived plasmablasts (PBs) and long-lived plasma cells (PCs). In secondary lymphoid organs, antigen-activated B cells differentiate into PBs. Some of these PBs home to bone marrow, where they differentiate into long-lived PCs. In bone marrow, PCs persist from a few months to years and secrete copious amounts of high-affinity antibodies which are central to the neutralization of pathogens. Therefore, understanding the molecular mechanisms underlying the development, survival and function of plasma cells is critical to designing better vaccines to generate effective immune responses. Ufm1 (ubiquitin-fold modifier 1) is a ubiquitin-like polypeptide that is post- translationally conjugated to target proteins via the ufmylation process and thereby modifies their function. Ufm1 binding protein (Ufbp1 or DDGRK1) is the first identified target of the ufmylation pathway. Ufl1 is the E3 ligase that attaches Ufm1 to Ufbp1. We published a novel role of Ufbp1 in development and function of ASCs. Consistent with this, mice lacking Ufbp1 in B cells have significantly reduced amounts of serum immunoglobulins and mount a highly defective antibody response against antigens. Aim 1 will use structure-function analysis to identify the regions of Ufbp1 that differentially regulate development of ASC and helps them to acquire the ability to produce antibodies. Aim 2 will test the roles of Ufm1 and Ufl1 pathway in development and function of ASCs. Aim3 will test the role of Ufbp1, Ufl1 and Ufm1 in promoting survival of long-lived PCs, maintaining their functionality and underlying molecular mechanisms. The outcome of the proposed study will provide an understanding of a novel molecular mechanism underlying Ufbp1-mediated promotion of antibody response and could potentially help in designing better vaccines and treatments for pathologies related to antibody secreting cells.