Ricerca di contatti, progetti,
corsi e pubblicazioni

ER-phagy mechanisms to maintain and restore endoplasmic reticulum homeostasis



Molinari M.



The endoplasmic reticulum (ER) is the site of folding and assembly for about a third of the eukaryote proteome. This membrane-bound organelle contains high concentrations of molecular chaperones and enzymes that 1) prevent aggregation of non-native newly synthesized polypeptides, 2) catalyze rate-limiting reactions of the protein folding process, and 3) insure that only native and fully-assembled proteins can leave the compartment to be transported to their intra- or extracellular functional site. The ER also contains molecular chaperones and enzymes that recognize terminally misfolded polypeptides and orphan subunits of oligomeric complexes, extract them from the folding environment and regulate their transport across the ER membrane for delivery into the cytosol where they are degraded by proteasomes. This process is known as ER-associated degradation (ERAD). Balanced activity of the ER folding and ERAD machineries is instrumental to maintain cellular homeostasis. A substantial increase in the ER cargo load, accumulation of misfolded polypeptides and environmental changes elicit an adaptation program known as the unfolded protein response (UPR). The UPR is triggered by ER stress sensors embedded in the ER membrane, and involves the activation of transcriptional/translational programs resulting in expansion of the ER volume, attenuated synthesis of ER cargo proteins and increased production of ER-resident chaperones and enzymes. Emerging evidence shows that the specific engulfment of part of the ER into autophagosomes through a selective type of autophagy, which has been named ER-phagy or reticulophagy, plays a key role in the maintenance of ER homeostasis in two important aspects of the cell response to ER stress. First, ER-phagy teams up with the ERAD machinery to clear accumulated protein aggregates from the ER. Second, it counteracts the uncontrolled expansion of the ER that occurs during ER stress. If UPR activation does not alleviate the ER stress or does not allow adaptation to it, cell death programs are activated. In contrast, if the cellular response relieves the stress condition, a recovery phase starts whereby the volume of the ER and the content of ER-resident proteins return to pre-stress levels. Our preliminary data lead us to propose a third role for ER-phagy in reducing the ER size and content during the recovery phase initiated upon termination of ER stress.

The major goal of this collaborative project is to identify the components and regulatory mechanisms underlying ER-phagy during cell recovery from ER stresses, which, to our knowledge, has remained totally unexplored until now. We will closely collaborate among 3 leading research groups, two in Switzerland and one in the Netherlands, to exploit our complementary experimental expertise and model systems (budding yeast and mammalian cells). Identified factors and principles will also be tested in the context of the two documented types of ER-phagy, i.e. clearance of ER aggregates and buffering ER expansion, to also shed light onto these poorly characterized processes and to determine whether ER-phagy operates through similar mechanisms under different stimulus conditions. Our studies will reveal important aspects of the coordinated cross talk between ER quality control, ER stress, ERAD and ER-phagy, which is crucial to maintain cell and organism homeostasis. The importance of these studies is highlighted by the growing interest and clinical use of proteostasis-modifying substances and autophagy modulators to contrast the onset and progression of several diseases caused by protein misfolding that leads to the accumulation of toxic aggregates.

Informazioni aggiuntive

Data d'inizio
Data di fine
36 Mesi
Enti finanziatori
Swiss National Science Foundation / Sinergia