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

分泌型抗体在中和病原体和保护宿主方面发挥着重要作用。 在B细胞反应中产生两种类型的ASCs：短寿命浆母细胞(PBS)和长寿命血浆 细胞(PC)。在次级淋巴器官中，抗原激活的B细胞分化为PBS。其中一些 PBS是骨髓的家园，在那里它们分化为长寿的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，这些抗体是 中和病原体。因此，了解潜在的分子机制 浆细胞的发展、存活和功能是设计更好的疫苗以产生 有效的免疫反应。Ufm1(泛素折叠修饰物1)是一种泛素样多肽，是一种后 通过超甲基化过程与目标蛋白翻译结合，从而改变它们的功能。 Ufm1结合蛋白(Ufbp1或DDGRK1)是ufm化途径的第一个被发现的靶点。Ufl1是 连接Ufm1和Ufbp1的E3连接酶。我们发表了Ufbp1在发育和功能中的新角色 ASCs。与此一致的是，B细胞中缺乏Ufbp1的小鼠的血清含量显著减少 免疫球蛋白，并对抗原产生高度缺陷的抗体反应。AIM 1将使用 结构-功能分析确定Ufbp1差异调控ASC发生的区域 并帮助它们获得产生抗体的能力。目标2将测试Ufm1和Ufl1的角色 ASCs的发育和功能途径。Aim3将测试Ufbp1、Ufl1和Ufm1在促进 长寿PC的生存，维持其功能和潜在的分子机制。这个 拟议的研究结果将提供对一种新的分子机制的理解 Ufbp1介导的抗体应答的促进作用，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.