The two UDPglucose::glycoprotein glucosyltransferase homologues play a protective role against ER stress and their expression is differentially regulated by progesterone

CASTRO, O.; ACOSTA, G.; RODRÍGUEZ SEGUÍ, S. A.; BUZZI, L.; BELEN PRADOS, M.; MIRANDA, S.

Bariloche

Simposio; Third South American Symposium in Signal Transduction and Molecular Medicine (SISTAM); 2015

American Society for Biochemistry and Molecular Biology (ASBMB) - International Union of Biochemistry and Molecular Biology (IUBMB)

It has long been recognized that some of the most prevalent human degenerativediseases appear as a result of the misfolding and aggregation of proteins.The formation of these protein aggregates play an important role in cell dysfunction and tissue damage leading to the disease. Recent evidence suggests that ER stress is also implicated in many chronic inflammatorydiseases such as irritable bowel syndromeand atherosclerosis. UGGT (UDP-Glc::glycoprotein glucosyltransferase), which has the ability to discriminate folded from misfolded glycoproteins, is the key component of the quality control mechanism of glycoprotein folding that ensure that only properly folded proteins exit the ER. Misfolded proteins are either retained within the ER or degraded by the proteasome. To characterize the physiopathologicalrole of UGGT1 and UGGT-2, their expression and biological role were explored in different experimental models. In most species of vertebrates and nematodes belonging to the genus Caenorhabditisthere are two homologues coding for UGGT-like proteins. We determined that CeUGGT-1 and CeUGGT-2are expressed during the entirelife cyclealthough at very different levels. Furthermore, we found that CeUGGT-2 is an essential protein and that the role of both CeUGGT-2 and CeUGGT-1 is significant in relieving low ER stress during development. We studied the body pattern expression of CeUGGT-1 and we found that it is expressed in the nervous system, pharynx and intestine, while CeUGGT-2 could not be detected under the same conditions.We also studied the expression and activity of UGGT-1 and UGGT-2 in a mouse hybridoma. Analysis of ChIP-seq datasets for PR ina a mammary cell line revealed that it binds UGGT2 promoter a that PR binds the UGGT2 promoter and also at a 3' putative regulatoryregion.Moreover, we found that the expression of each isoform is differentially regulated by highphysiological progesterone concentrations and that this process is differentially mediated by both nuclear and gamma membrane progesterone receptor.We are currently studying the expression of both enzymes in normal human brains and in those derived from patients which have developed different degenerative proteinophaties.