Rapidly Degraded Polypeptides in Protein Quality Control

描述（由申请人提供）：新翻译多肽的降解是蛋白质质量控制的一个鲜为人知的组成部分。在真核细胞中，多达30%的新生多肽迅速降解，半衰期约为10分钟。为什么细胞会产生那么多迅速被破坏的多肽？对这种快速降解的易感性并不取决于蛋白质通常确定的半衰期（t1/2）。因此，新生的蛋白质分子可以折叠形成稳定的形式（t1/2 = 1-2天，平均），也可以直接进入快速降解的多肽（RDP）池（t1/2 = -10分钟）。由于rdp来源于新合成的多肽，我们假设rdp代表了蛋白质质量控制的关键中间体。rdp最早是在抗原呈递研究中发现的，因为它们是主要组织相容性复合体I类（MHC I类）分子呈递肽的主要来源。由于MHC I结合肽主要来源于rdp，翻译和MHC I呈递紧密耦合。这种耦合使细胞毒性T淋巴细胞能够在病毒劫持细胞翻译机制时迅速检测到。因此，我们预计，了解rdp的生物学将导致对适应性免疫的有价值的见解，并提高我们设计引发最佳免疫反应的疫苗的能力。rdp很难研究，因为根据定义，它们是不稳定的。我们提出了一种利用编码抗原肽的报告基因直接研究rdp的新方法。我们将利用这一报告人制度来调查RDP生产的监管情况。公共卫生相关性：我们提出的研究将探索导致新合成蛋白质快速破坏的机制。这项研究将促进疫苗设计的改进，并可能导致治疗遗传疾病的新方法。

DESCRIPTION (provided by applicant): The degradation of newly translated polypeptides is a poorly understood component of protein quality control. In eukaryotic cells, up to 30% of all nascent polypeptides are rapidly degraded with a half-life of ~10 minutes. Why do cells make so many polypeptides that are rapidly destroyed? Susceptibility to this rapid degradation does not depend on the usual, established half-life (t1/2) of a protein. Thus, a nascent protein molecule can either fold to yield a stable form (t1/2 = 1-2 days, on average) or be directed to the rapidly degraded polypeptide (RDP) pool (t1/2 = -10 minutes). Because RDPs derive from newly made polypeptides, we hypothesize that RDPs represent a critical intermediate in protein quality control. RDPs were first discovered in studies of antigen presentation, because they are the predominant source of peptides presented on major histocompatibility complex class I (MHC class I) molecules. Because MHC I- bound peptides derive primarily from RDPs, translation and MHC I presentation are tightly coupled. This coupling allows cytotoxic T lymphocytes to quickly detect when a virus has hijacked the cellular translation machinery. Therefore, we anticipate that understanding the biology of RDPs will lead to valuable insights into adaptive immunity and improve our ability to design vaccines that elicit optimal immune responses. RDPs are difficult to study because they are, by definition, unstable. We propose a novel approach to study RDPs directly using a reporter encoding an antigenic peptide. We will apply this reporter system to investigate the regulation of RDP production. Public Health Relevance: Our proposed research will explore the mechanisms that lead to the rapid destruction of newly made proteins. This research will facilitate improvements in vaccine design and potentially lead to new approaches for the treatment of genetic diseases.