THE TWO UDPGLUCOSE::GLYCOPROTEIN GLUCOSYLTRANSFERASES HOMOLOGUES PLAY A PROTECTIVE ROLE AGAINST ER STRESS AND THEIR EXPRESSION IS DIFFERENTIALLY REGULATED BY PROGESTERONE

CASTRO O. A; ACOSTA MONTALVO ANA GABRIELA; SANTIAGO A RODRÍGUEZ-SEGUÍ; LUCILA BUZZI; M. BELÉN PRADOS; SILVIA MIRANDA

Bariloche

Congreso; SISTAM 2015; 2015

The Third South American Symposium in Signal Transduction and Molecular Medicine

It has long been recognized that some of the most prevalent human degenerativediseases appear as a result of the misfolding and aggregation of proteins. Theformation of these protein aggregates play an important role in cell dysfunction andtissue damage leading to the disease. Recent evidence suggests that ER stress is alsoimplicated in many chronic inflammatory diseases such as irritable bowel syndromeand atherosclerosis. UGGT (UDP-Glc::glycoprotein glucosyltransferase), which has theability to discriminate folded from misfolded glycoproteins, is the key component ofthe quality control mechanism of glycoprotein folding that ensure that only properlyfolded proteins exit the ER. Misfolded proteins are either retained within the ER ordegraded by the proteasome. To characterize the physiopathological role of UGGT1and UGGT-2, their expression and biological role were explored in differentexperimental models. In most species of vertebrates and nematodes belonging to thegenus Caenorhabditis there are two homologues coding for UGGT-like proteins. Wedetermined that CeUGGT-1 and CeUGGT-2 are expressed during the entire life cyclealthough at very different levels. Furthermore, we found that CeUGGT-2 is anessential protein and that the role of both CeUGGT-2 and CeUGGT-1 is significant inrelieving low ER stress during development. We studied the body pattern expressionof CeUGGT-1 and we found that it is expressed in the nervous system, pharynx andintestine, while CeUGGT-2 could not be detected under the same conditions. We alsostudied the expression and activity of UGGT-1 and UGGT-2 in a mouse hybridoma.Analysis of ChIP-seq datasets for PR in a mammary cell line revealed that it bindsUGGT2 promoter and also at a 3' putative regulatory region. Moreover, we found thatthe expression of each isoform is differentially regulated by high physiologicalprogesterone concentrations and that this process is differentially mediated by bothnuclear and gamma membrane progesterone receptor. We are currently studying theexpression of both enzymes in normal human brains and in those derived frompatients which have developed different degenerative proteinophaties.