Sorting and shedding of GPI proteins

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Proteins that are exported out of the cell must be sorted out from other proteins and must properly fold within the endoplasmic reticulum (ER) before their intracellular transport to the cell surface can take place. The cell has elaborated a sophisticated mechanism called the 'unfolded protein response' to eliminate proteins that cannot adopt their proper structure. A salient feature of this quality control mechanism is the targeting and degradation of misfolded proteins by the ER-associated degradation pathway. Pathological conditions can lead to the sustained activation of the 'unfolded protein response' and, inability of the cell to eliminate misfolded proteins is believed to cause neurodegenerative diseases and type II diabetes. Our laboratory is using the brewer yeast S. cerevisiae as a model organism to study fundamental aspects related to the sorting and quality control mechanism of a particular class of membrane proteins called GPI proteins, which associate to specialized membrane microdomains rich in cholesterol and sphingolipid (so called 'lipid rafts'). In the past few years we provided evidence that the GPI protein named Yps1p, which is part of a family of fungal enzymes present at the cell surface, appears to be maintained segregated apart form other membrane proteins during its intracellular transport to the cell surface. We also showed that Yps1p plays a role in the elimination of GPI proteins at the cell surface during the unfolded protein response. Importantly, we also provided evidence that in conditions of lipid imbalance, in the absence of misfolded proteins within the ER, GPI proteins are eliminated from the cell surface by a novel quality control mechanism implicating phospholipases. This novel mechanism is linked to the 'unfolded protein response', but it is not clear how. In the current proposal, we have designed experiments to establish how this novel quality control mechanism and the 'unfolded protein response' are connected. We also propose to further document how Yps1p recognizes and eliminates GPI proteins during the 'unfolded protein response'. The proposed studies should deepen our understanding on how GPI proteins are sorted from other membrane proteins and should help elucidating what triggers the 'unfolded protein response' in conditions of lipid imbalance, in the absence of misfolded proteins.