The endoplasmic reticulum (ER) is the primary site for the biogenesis of membrane and secretory proteins. Folding and maturation of proteins in the ER is an elaborate process that frequently involves a number of posttranslational modifications (like disulfide bond formation, glycosilation, lipidation, etc) and/or assembly in protein complexes. The ER is also involved in the synthesis of most of the lipids in cells. Perturbations of any of these processes often results in ER stress, a hallmark of many diseases including diabetes, obesity and cancer.
Our long-term goal is to understand the mechanisms underlying ER homeostasis with emphasis on the following topics:
- Molecular mechanisms of ER- associated protein degradation (ERAD)
Quality control mechanisms allow only fully folded proteins to leave the ER and travel along the secretory pathway, thus ensuring the fidelity of plasma membrane and secreted proteins through which cells communicate with their environment. Misfolded proteins in the lumen or membrane of the ER are discarded by ER-associated protein degradation (ERAD), a pathway in which misfolded proteins are recognized, translocated across ER membrane (retrotranslocated), ubiquitinated and released in the cytosol for proteasomal degradation. In the recent years, we and others identified several components involved in ERAD and some aspects of the pathway have been clarified. Despite this progress, the molecular mechanisms of ERAD are still largely unknown. Key unresolved issues under investigation in our lab include the determinants for substrate selectivity and the mechanism for translocation of misfolded proteins across the ER membrane.
- Lipid droplets biogenesis and dynamics
Cytoplasmic lipid droplets are depots of neutral lipids (triglycerides, cholesterol esters) enclosed in a monolayer of phospholipids and associated proteins. These organelles appear to be extremely dynamic however they maintain a very intimate relation with the ER. In fact, the prevailing model for lipid droplet biogenesis involves the budding of the nascent lipid droplet from the ER. Lipid droplets are present in most eukaryotic cells where they may serve as reservoirs to store cellular energy and as building blocks for membrane lipids. Excessive lipid accumulation in cells is also the hallmark of obesity and atherosclerosis, but remarkably little is known about lipid-droplet cell biology.
Among the questions we are trying to address are the mechanisms involved in lipid droplet formation and how proteins are targeted to these organelles.
We are studying these processes using a combination of biochemical, genetic and imaging approaches using the budding yeast
Sacharomyces cerevisiae, as a model system.
Last modification:
26/02/2010
