Collagen and chylomicron homeostasis
EU-LIFE Science Newsletter 3/2017
Latest News from the Centre for Genomic Regulation (CRG), Spain
28 different kinds of collagens constitute about 25% of our dry body weight and are the main ingredients of connective tissue. More than 1,000 mutations in collagens have been identified in a variety of human diseases. CRG scientists explain their latest results on understanding how collagens are secreted and exported in the cell.
28 different kinds of collagens constitute about 25% of our dry body weight and are the main ingredients of connective tissue. More than 1,000 mutations in collagens have been identified in a variety of human diseases. An understanding of how these proteins are produced, secreted and assembled into a functional extracellular matrix is therefore an important challenge.
This is in contrast to our rich comprehension of the general pathway and mechanism of protein secretion. The reason being that collagens are too bulky to fit into COPII vesicles that export secretory cargoes after their synthesis in the endoplasmic reticulum (ER). Secreted Apo-B coated lipoproteins (chylomicrons and very low density lipoproteins) are essential for dietary lipid homeostasis by transporting them from intestine to other tissues in the body. The problem with the export of chylomicrons and lipoprotein particles in general is the same: they are too big to fit into the generic COPII vesicles. So how are these two classes of molecules, collagens and chylomicrons, secreted?
We performed a genome wide screen in metazoan cells and discovered a number of new genes that were required for transport and Golgi organization (TANGO genes). One of these genes, TANGO1, was found to be essential for export of collagen VII from the ER and more recent data from many labs suggest that TANGO1 is required for secretion of many other collagens. In fact, in a mouse model of fibrosis, siRNA based knockdown of TANGO1, is reported to inhibit development of this pathology in hepatic fibrosis by affecting secretion of collagen I.
Together these findings suggest that TANGO1 is a key player in the process of collagen export from the ER, and it can be used as a means to control pathologies associated with hypo- and hyper secretion of collagens. We discovered a TANGO like protein, TALI, that is expressed in cells of the liver and small intestine, and showed that it controls the export of chylomicrons and very low density lipoproteins from the ER. TANGO1 and TALI bind to their respective cargoes in the lumen of ER and by a novel mechanism promote the growth of transport carrier for on the cytoplasmic side of the ER. The discovery of TANGO1 and TALI provides a means to dissect the mechanism of collagens and lipoprotein particles homeostasis.
Original article: Raote, I., Ortega Bellido, M., Pirozzi, M., Zhang, C., Melville, D., Parashuraman, S., Zimmermann, T., Malhotra, V. (2017) TANGO1 assembles into rings around COPII coats at ER exit sites. J Cell Biol. 216(4):901-909.
Image: TANGO1 rings encircle vesicles budding from the ER. Credit: Ishier Raote, CRG
