MOLECULAR CHAPERONES AND IG BIOSYNTHESIS

描述(改编自调查人员摘要)：正常的发展和 免疫系统的功能在一定程度上取决于适当的组装和 免疫球蛋白(Ig)受体和分泌蛋白的表达。像所有人一样 合成、折叠和组装分泌途径蛋白、Ig分子 在内质网(ER)中，但与大多数异构体蛋白不同，有 是一种亚基表达的发育不对称。分子 内质网的伴侣蛋白在控制细胞的折叠过程中起着关键作用 单个亚基和确保未完全或不正确组装的Ig 蛋白质不会离开这个细胞器。因此，通过以下方式阐明其机制 内质网中哪种免疫球蛋白的成熟受控制对于理解 保证了免疫系统的正常发育。在过去，Ig Heavy 轻链也提供了一个很好的模型系统来识别 ER质量控制系统的组成部分以及了解其 功能。在上一次资助期间，我们的研究显示，免疫球蛋白 传输是在域折叠的级别上控制的，与其他 未折叠的蛋白质、未组装的重链似乎不会循环 呃，陪护。为了了解负责的细胞结构 为此，在本申请中提出了实验以1)确定 GRP94(一种功能未知的主要内质网伴侣)在维持体重中的作用 处于能够与轻链组装的展开状态的链， 2)鉴定和鉴定调节Bip ATPase循环的ER蛋白， 一个内质网伴侣，以了解为什么它稳定地与Ig Heavy结合 在没有轻链合成的情况下，以及3)分离ER同系物 DNAJ伴侣辅助因子，帮助和稳定结合 HSP70分子伴侣到未折叠的蛋白质以了解Bip如何与重蛋白结合 链条受到控制。从本文件中概述的实验中获得的数据 建议将增加我们对ER质量控制机制的了解 这对免疫球蛋白的生物合成和成熟至关重要。

DESCRIPTION (adapted from investigator's abstract): The normal development and function of the immune system is dependent, in part, on the proper assembly and expression of immunoglobulin (Ig) receptor and secreted proteins. Like all secretory pathway proteins, Ig molecules are synthesized, folded and assembled in the endoplasmic reticulum (ER), but unlike most heteromeric proteins, there is a developmental asymmetry in the expression of the subunits. The molecular chaperones of the ER play a critical role in controlling the folding of the individual subunits and ensuring that incompletely or improperly assembled Ig proteins do not leave this organelle. Therefore, elucidating the mechanisms by which Ig maturation in the ER is controlled is important to understanding how the proper development of the immune system is ensured. In the past, Ig heavy and light chains have also provided an excellent model system for identifying components of the ER quality control system and for understanding their function. During the last funding period, our studies revealed that Ig transport is controlled at the level of domain folding and that unlike other unfolded proteins, unassembled heavy chains do not appear to cycle on and off ER chaperones. To understand the cellular machinery that is responsible for this, experiments are proposed in the present application to 1) determine the role of GRP94 (a major ER chaperone of unknown function) in maintaining heavy chains in an unfolded state that is competent for assembly with light chains, 2) identify and characterize ER proteins that regulate the ATPase cycle of BiP, an ER chaperone, in order to understand why it remains stably bound to Ig heavy chains in the absence of light chain synthesis, and 3) isolate ER homologues of the DnaJ chaperone cofactor, which acts to aid and stabilize the binding of hsp70 chaperones to unfolded proteins to understand how BiP's binding to heavy chains is controlled. The data obtained from the experiments outlined in this proposal will increase our understanding of the ER quality control machinery that is so crucial to proper Ig biosynthesis and maturation.