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

需要结构蛋白、受体或酶的有效区室化以确保细胞的完整性。蛋白质带有信号，使它们能够到达细胞内的适当位置。 在运输囊泡的形成过程中，货物 * 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。这是例如一些细胞表面受体的情况，这些受体仅在它们组装成多分子复合物后才起作用。这些复合物的亚单位含有特定的信号，这些信号将它们保留在内质网中，直到它们全部正确结合。突变扰乱了这些信号在分子中的功能，如离子转运蛋白或神经递质的膜受体，具有重要的后果并导致疾病。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，这种蛋白质参与了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，我们将表征与不变链相互作用并影响其亚细胞定位的分子的作用。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，追求细胞内运输和宿主-病原体相互作用的表征。 阐明分选 * 信号的作用模式将有助于理解其在蛋白质中的一般调控，但也可能突出免疫系统缺陷 * 的基础，这在糖尿病和某些白血病等疾病中特别有趣，因为这些疾病中 * 不变链表达异常。该项目将对我们理解调节蛋白质细胞内分选和多聚体复合物或受体组装的机制产生重大影响。此外，我们的研究结果应该深化无处不在的COPII复合物的 * 表征。最后，我们将收集有价值的结构信息的 * 组装和成熟的不变链。这将有助于开发疫苗或移植和自身免疫的新治疗途径。

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.**