Proteostasis in the early secretory compartment as a pathogenetic mechanism and therapeutic target

Like big cities, our cells are extremely crowded and divided in specialized districts, separated by impermeable membranes. In this complicated network, each newly made component must be efficiently dispatched to its final destination for cells to function properly. Moreover, our cells are capable of sorting proteins that attained a correct conformation from misfolded or aberrant species, retaining and destroying the latter (quality control). Targeting and sorting mistakes are dangerous and can kill cells.Molecular and cell biologists are unravelling the mechanisms regulating the quality control and intracellular traffic of proteins. This is having an enormous impact on genetic diseases, many of which arise because the gene product, a protein, cannot reach the district where it is needed (loss of function) or is marooned along its way, causing traffic jams that can damage and eventually kill cells (gain of toxic function). Our project aims at understanding how cells manage to produce, sort and release impressive quantities of proteins of the highest quality, discarding the bad ones. Only if we comprehend in detail the underlying mechanisms, we'll be able to decipher the molecular pathogenesis of different genetic diseases, design strategies and drugs able to restore proper protein delivery, and relieve the toxicity due to traffic jams in and between cells. By defining key regulatory mechanisms governing quality and efficiency of secretion, moreover, our studies may contribute to improve production of recombinant proteins for cell and replacement therapy, to be used in diverse genetic disorders.