Protein folding, quality control and degradation in the endoplasmic reticulum

Secretory, membrane-bound and organelle proteins (i.e., about 30% of the eukaryotic cell proteome) are co- or post-translationally translocated into the endoplasmic reticulum (ER). ER-resident molecular chaperones, folding, quality control and degradation factors insure maintenance of cell, tissue and organism proteostasis by catalyzing rate-limiting reactions of protein folding programs, by inspecting the final shape of newly synthesized polypeptides, by selecting for degradation terminally misfolded proteins and by allowing transport at the site of activity of native, fully assembled and functional ones. The aim of the research performed in our group is to understand how mammalian cells insure expression of the cellular proteome and how they respond to variations in ER homeostasis and in ER load with folding-defective or folding-competent polypeptides. To address these questions, we have generated plasmids and cell lines for transient, stable, inducible and tunable expression of a collection of model polypeptides. Their different topology, folding-capacity, aggregation proneness, structural features, expression levels lead to engagement of specific folding, quality control, degradation and cell adaptation pathways to be characterized in molecular details in our lab. We are in the best position to study the known pathways operating to maintain cellular proteostasis, i.e., the appropriate quality and quantity of the proteome, and to characterize new ones. The ongoing collaborations with Francesco Bertoni (Institute of Oncology Research, Bellinzona, transcriptomic), Paola Picotti (ETH-Zurich, proteomic) and Manfredo Quadroni (UNI-Lausanne, interactomic) are thought to give essential contributions to our research as detailed in the Research Plan. The results of our studies may eventually lead to the development of strategies to manipulate protein folding, quality control and degradation events. Also sought-after is the capacity to intervene to modulate cell responses to expression of mutant gene products with specific structural defects thereby contrasting progression or even cure proteopathies caused by inefficient functioning of the cellular protein factory. A better comprehension of the cellular protein factory will also improve our capacity to produce high amounts of active recombinant proteins to be employed in the clinics and in the industry.