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

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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.**