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

CASTRO OA; ACOSTA AG; BUZZI LI; PRADOS, B; MIRANDA S

Bariloche

Simposio; SISTAM2015; 2015

American Society for biochemistry and Molecular Biology, International Union for Biochemisty and Molecular Biology

It has long been recognized that some of the most prevalent human degenerative diseases 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. Prion protein, amyloid-beta, alpha-synuclein, serum amyloid A and islet amyloid polypeptide are some of the proteins that trigger disease when they get misfolded. Recent evidence suggests that ER stress is also implicated in many chronic inflammatory diseases such as irritable bowel syndrome, and atherosclerosis. The 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 subject to degradation by the proteasome. In most species of vertebrates and at least in nematodes belonging to the genus Caenorhabditis are two homologues coding for UGGT-like proteins. We decided to further characterize the significance of the UGGT1 and elucidate the role of UGGT-2 in this multicellular organism. We determined that both CeUGGT-1 and CeUGGT-2 are expressed during the entire life cycle although at very different levels. Furthermore, we found that CeUGGT-2 is an essential protein and that the role of CeUGGT-2 but not CeUGGT-1 is significant in relieving low ER stress during development. Using the fosmid recombineering technique we study the body pattern expression of both proteins and found that CeUGGT-1 is expressed in the nervous system, pharynx and intestine, while CeUGGT-2 could not be detected under the same conditions. We are currently study the expression of both enzymes in human brains derived from patients which have developed different degenerative proteinophaties. We also study the expression and activity of human UGGT-1 and UGGT-2 in a mouse hybridoma. Bioinformatics studies showed that there is strong progesterone responding element present in the UGGT-2 promotor. We found that the expression of each isoform is differentially regulated by high physiological progesterone concentrations and that this process is mediated by the gamma membrane progesterone receptor.