Characterization of the di-arginine (R-x-R) endoplasmic reticulum retention signal in health and disease.

健康和疾病中双精氨酸 (R-x-R) 内质网滞留信号的表征。

• 批准号: RGPIN-2015-04821
• 负责人: Thibodeau, Jacques
• 金额: $ 2.48万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613190
• 关键词: Characterization; di; arginine; endoplasmic; reticulum

Efficient compartmentalization of structural proteins, receptors or enzymes is needed to ensure cellular integrity. Proteins bear signals that allow them to reach their proper location inside the cell. During formation of transport vesicles, cargo selection is achieved by chaperones (coat proteins) interacting with specific amino acid motifs embedded in the proteins. However, the transport of some proteins must be prevented until they are correctly assembled. This is the case for example of some cell surface receptors that  are functional only after their assembly into multimolecular complexes. The subunits of these complexes  contain specific signals that retain them in the endoplasmic reticulum until they have all properly associated. Mutations that perturbed the function of these signals in molecules such as ion transporters or membrane receptors for neurotransmitters have important consequences and lead to disease. We are addressing the function of such an endoplasmic reticulum retenton motif in a protein called invariant chain, which is involved in the immune response against pathogens and tumours. Using biochemistry, cell biology and immnology techniques, we will characterize the role of molecules that interact with the invariant chain and affect its sub-cellular localization. Interestingly, we have recently demonstrated that certain virulence products produced by some pathogenic bacteria will disturb the intracellular trafficking of invariant chain by inhibiting the formation of transport vesicles called COPII. This finding offers a molecular handle to pursue the characterization of intracellular transport and of host-pathogens interactions.  Clarifying the mode of action of the sorting signal will help understanding its regulation in proteins in general but might also highlight the basis for defects in the immune system.This is especially interesting in pathologies such as diabetes and some leukemias where the invariant chain expression is aberrant. This project will have a major impact on our understanding of the mechanisms regulating intracellular sorting of proteins and assembly of multimeric complexes or receptors. In addition, our results should deepen the characterization of the ubiquitous COPII complex. Finally, we will gather valuable structural information on the assembly and maturation of invariant chain. This should help in the development of vaccines or new therapeutic avenues in transplantation and autoimmunity.

需要结构蛋白、受体或酶的有效区室化，以确保细胞内 完整 蛋白质带有信号，使它们能够到达细胞内的适当位置。在运输囊泡形成期间， 选择是通过分子伴侣（外壳蛋白）与嵌入蛋白质中的特定氨基酸基序相互作用来实现的。然而，必须防止某些蛋白质的运输，直到它们正确组装。例如，一些细胞表面受体只有在组装成多分子复合物后才有功能。这些复合物的亚基含有特定的信号，这些信号将它们保留在内质网中，直到它们全部正确结合。在分子如离子转运蛋白或神经递质的膜受体中扰乱这些信号的功能的突变具有重要的后果，并导致神经递质的突变。疾病 我们正在研究这种内质网滞留基序在一种称为不变链的蛋白质中的功能， 参与对病原体和肿瘤的免疫反应。利用生物化学，细胞生物学和免疫学技术，我们将描述与不变链相互作用并影响其亚细胞的分子的作用。 本地化有趣的是，我们最近已经证明，某些致病菌产生的某些毒力产物会通过抑制称为COPII的运输囊泡的形成来干扰不变链的细胞内运输。这一发现提供了一个分子处理，以追求细胞内运输和宿主-病原体相互作用的表征。 信号将有助于理解其在蛋白质中的调控，但也可能突出缺陷的基础 在免疫系统中。这在糖尿病和一些白血病等病理中特别有趣， 不变链表达式是异常的。 这个项目将对我们理解调节细胞内分选的机制产生重大影响 蛋白质和多聚体复合物或受体的组装。此外，我们的成果应深化 普遍存在的COPII复合物的表征。最后，我们将收集有关 不变链的组装和成熟。这将有助于开发疫苗或新的 移植和自身免疫的治疗途径。