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

需要对结构蛋白、受体或酶进行有效的区隔，以确保细胞 正直。 蛋白质携带的信号允许它们到达细胞内合适的位置。在运输囊泡形成过程中，货物 选择是通过伴侣(外壳蛋白)与蛋白质中嵌入的特定氨基酸基序相互作用实现的。然而，必须阻止某些蛋白质的运输，直到它们被正确组装。例如，一些细胞表面受体只有在组装成多分子复合体后才能发挥功能。这些复合体的亚单位可能包含特定的信号，将它们保留在内质网中，直到它们都正确地关联起来。扰乱这些信号在分子中的功能的突变，如离子转运体或神经递质的膜受体，会产生重要的后果并导致疾病。 我们正在研究这样一个内质网保留基序在一种名为不变链的蛋白质中的功能，它 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，我们最近证明了某些致病菌产生的某些毒力产物会通过抑制被称为COPII的运输小泡的形成来干扰细胞内不变链的运输。这一发现为探索细胞内运输和宿主与病原体相互作用的特征提供了一个分子句柄，并澄清了分选的作用模式。 Signal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疾病中尤其有趣 不变链的表达是异常的。 这个项目将对我们理解细胞内分选的调节机制产生重大影响 蛋白质和多聚体复合体或受体的组装。此外，我们的结果应该会加深 无处不在的COPII复合体的特征。最后，我们将收集有关 不变链的组装和成熟。这应该有助于疫苗或新疫苗的开发 移植和自身免疫的治疗途径。

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.