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

分泌的抗体在中和病原体和保护宿主方面起着重要作用。 在B细胞应答期间形成两种类型的ASC：短寿命浆母细胞（PB）和长寿命浆母细胞（PB）。 细胞（PC）。在次级淋巴器官中，抗原活化的B细胞分化为PB。其中一些 PB回到骨髓，在那里它们分化成长寿的PC。在骨髓中，PC从 几个月到几年，并分泌大量的高亲和力抗体，这是核心的 中和病原体。因此，了解这些疾病的分子机制， 浆细胞的发育、存活和功能对于设计更好的疫苗以产生 有效的免疫反应。Ufm 1（ubiquitin-fold modifier 1）是一种泛素样多肽， 通过磺酰化过程与靶蛋白偶联，从而改变其功能。 Ufm 1结合蛋白（Ufbp 1或DDGRK 1）是Ufmylation途径的第一个鉴定的靶点。Ufl 1是 将Ufm 1连接到Ufbp 1的E3连接酶。我们发表了Ufbp 1在发育和功能中的新作用， 的ASC。与此相一致，B细胞中缺乏Ufbp 1的小鼠血清中 免疫球蛋白，并产生针对抗原的高度缺陷的抗体应答。目标1将使用 结构-功能分析以鉴定差异调节ASC发展的Ufbp 1区域 帮助它们获得产生抗体的能力。目标2将测试Ufm 1和Ufl 1的作用 ASCs的发育和功能。Aim 3将测试Ufbp 1、Ufl 1和Ufm 1在促进 长寿命PC的生存，维持其功能和潜在的分子机制。的 拟议的研究结果将提供一个新的分子机制的理解， Ufbp 1介导的抗体应答促进作用可能有助于设计更好的疫苗 以及与抗体分泌细胞相关的病理的治疗。

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.