Identification of the mechanisms of unconventional.. (UnProSec)
Identification of the mechanisms of unconventional protein secretion: AP2, a new protein secreted by this unknown pathway
Start date: May 15, 2014,
End date: May 14, 2017
Most of the secreted proteins transit into and through the endoplasmic reticulum (ER) and the Golgi apparatus. However, eukaryotic cells secrete a class of proteins, which do not enter the ER. Very little is known about this “unconventional secretory pathway”. The last protein identified to be secreted by this pathway is AP2, a cytoplasmic fatty acid-binding protein, which is secreted unconventionally by adipocytes to control glucose liver metabolism. It was reported that the unconventional secretion of Acb1 from Saccharomyces cerevisiae requires diverse group of proteins including GRASP ortholog Grh1, autophagy-related proteins, proteins involved in fusion of membranes with endosomes, members of the ESCRT-machinery, and the plasma membrane t-SNARE Sso1. The requirement of GRASP and autophagy-related proteins has also been reported to be required for the unconventional secretion of IL-1beta, IL-18 and HMGB1 in mammalian cell. How these proteins work together for the unconventional secretory pathway remains elusive. We hypothesize that this process is mediated by a secretory autophagosome and our goal is to reveal the mechanism of this secretory process.We aim to proof this by assessing three main objectives. First, I aim at identifying new proteins require for AP2 secretion. Second, I aim at characterizing morphologically and biochemically the vesicular intermediates required for AP2 secretion. Third, I aim at isolating vesicular intermediates containing AP2 to identify their polypeptide composition.Our approach should allow us to reveal a number of new proteins involved in the process of unconventional proteins secretion as well as the mechanisms of biogenesis, transport and fusion with the membrane of the vesicular intermediates required for this process. The understanding of the mechanisms involved in AP2 secretion is of fundamental importance and can have a significant impact on the understanding of a wide variety of human metabolic diseases.
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