From Unfolded Proteins in the ER to Disease

描述（由申请人提供）：在真核细胞中，用于细胞表面或外部环境的蛋白质首先转运到内质网（ER），在内质网中发生初始蛋白质折叠和修饰，这对于蛋白质在转运到细胞表面之前获得适当的功能构象是必不可少的。人们早就知道，初级氨基酸序列的突变可导致蛋白质错误折叠，并有助于疾病的发病。然而，现在越来越明显的是，在许多情况下，疾病状态不仅仅是蛋白质功能丧失的结果，而是经常涉及容纳蛋白质错误折叠的细胞过程。细胞通过调节一些基本的细胞过程，包括基因表达、mRNA翻译和蛋白质降解，来适应内质网中错误折叠蛋白的积累。我们现在对细胞如何协调这些适应性反应的理解有了重大突破。如果适应不充分，细胞进入凋亡死亡途径。最近的研究表明，蛋白质错误折叠不仅是基因突变的结果，也是各种环境损害的结果，包括但不限于代谢改变、病毒感染、氧化应激和高胆固醇血症，以及在衰老过程中经常发生的处理这些条件的能力改变。最后，许多高度分化的细胞类型，如胰腺β细胞和浆细胞，需要信号通路来适当协调蛋白质的表达和分泌与内质网蛋白折叠能力。随着我们对内质网中蛋白质错误折叠的适应性和凋亡反应的了解越来越多，很明显，这些事件有助于许多疾病状态的病理。本次会议将集中讨论我们对蛋白质生物合成、折叠、降解的复杂性的理解的最新进展，以及通过新的遗传、生化和细胞生物学方法发现的早期分泌途径中错误折叠蛋白质积累的细胞反应。此外，它还将重点介绍由蛋白质折叠紊乱引起的广泛疾病的研究，以及预防或纠正错误折叠方法的最新进展。确定细胞适应和屈服于蛋白质折叠缺陷的机制，以及开发这些过程的治疗上有用的抑制剂或激活剂，可能对各种疾病产生巨大影响，包括阿尔茨海默病、心血管疾病、糖尿病、传染病、癌症和其他与正常衰老过程相关的疾病。

DESCRIPTION (provided by applicant): In eukaryotic cells, proteins destined for the cell surface or for the external milieu are first translocated into the endoplasmic reticulum (ER) where initial protein folding and modifications occur that are essential for the protein to attain its appropriate functional conformation prior to transit to the cell surface. It has long been known that mutations in the primary amino acid sequence can cause protein misfolding and contribute to disease pathogenesis. However, it is now becoming evident that in many cases disease states are not simply a result of protein loss of function, but rather frequently involve cellular processes that accommodate protein misfolding. Cells adapt to the accumulation of misfolded proteins in the ER by regulating several fundamental cellular processes including gene expression, mRNA translation, and protein degradation. We have now experienced significant breakthroughs in our understanding of how cells coordinate these adaptive responses. If adaptation is not adequate, cells enter an apoptotic death pathway. Recent studies reveal that protein misfolding results not only from gene mutations but also arises as a consequence of a variety of environmental insults including but not limited to altered metabolism, viral infection, oxidative stress, and hypercholesterolemia, as well as the altered ability to deal with these conditions that often occur during aging. Finally, many highly differentiated cell types, such as pancreatic beta cells and plasma cells, require signaling pathways to properly coordinate protein expression and secretion with the ER protein folding capacity. As we understand more about the adaptive and apoptotic responses to protein misfolding in the ER, it is evident that these events contribute to the pathology of numerous disease states. This conference will focus on recent advances in our understanding of the complexities of protein biosynthesis, folding, degradation, and cellular responses to the accumulation of misfolded proteins in the early secretory pathway as discovered through novel genetic, biochemical, and cell biological approaches. In addition, it will highlight studies on a broad collection of diseases that are caused by protein folding disorders and recent advances in approaches to prevent or correct misfolding. Identifying the mechanisms by which cells adapt and succumb to protein folding defects and the development of therapeutically useful inhibitors or activators of these processes are likely to have a tremendous impact on a variety of diseases including Alzheimer's disease, cardiovascular disease, diabetes, infectious diseases, cancer, and other diseases associated with the normal aging process. PUBLIC HEALTH RELEVANCE: It is now appreciated that protein misfolding in the endoplasmic reticulum contributes to a variety of human diseases ranging from metabolic and genetic disorders to cancer and heart disease, as well as to a number of conditions associated with normal aging processes. In fact studies indicate that the cellular folding machinery and quality control systems that oversee them decline with age, which further contributes to the problem. The goal of this FASEB meeting is to provide a venue for reporting cutting edge research findings and for promoting the free exchange of scientific information between investigators from multiple disciplines. This meeting will increase our understanding of the molecular mechanisms that regulate protein folding in the ER and should lead to the identification of critical targets for the prevention, diagnosis and/or treatment of human diseases.