Dana 18. Kolovoza 2008, u 10:00, na MedILS-u, Split odrzati ce se predavanje postdoktorantice Kristine Oresic, Dept. of Microbiology, Mount Sinai School of Medicine, New York.

Naslov predavanja:

"Retrograde transport of proteins across the endoplasmic reticulum membrane"

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Kristina Oresic, PhD

Dept. of Microbiology, Mount Sinai School of Medicine, New York

"Retrograde transport of proteins across the endoplasmic reticulum membrane"

Eukaryotic proteins destined for cell surface expression, secretion, or those whose site of action is within the secretory pathway are co-translationally synthesized in the ER.  The ER has in place multiple mechanisms of quality control to ensure that nascent polypeptides achieve their proper conformation. ER quality control enables eukaryotic cells to remove aberrant ER polypeptides that did not achieve a native conformational state. These proteins are extracted from the ER through an aqueous pore denominated dislocon by a process referred to as dislocation. Upon exposure to the cytosol, the polypeptides are deglycosylated by N-glycanase and finally targeted for the proteasomal degradation.
By using different approaches our laboratory tries to elucidate the mechanism of retrograde transport and identify cellular components that participate or facilitate this process. For example, the human cytomegalovirus proteins US2 and US11 utilize the ER-to-cytosol extraction process to facilitate the evasion of immune response. They both independently target MHC class I for the proteasomal degradation and allow for the virus to avoid immune detection and clearance. Using US2- and US1l-expressing cells, we examined the role of TRAM1, an ER protein involved in processing nascent polypeptides, in the dislocation of class I molecules and proposed a model in which TRAM1 plays an important role in the dislocation of ER glycoproteins. Furthermore, we have demonstrated that this process is mediated by specific chaperone-complex comprised of Bip, calnexin and calerticulin. 
In addition our lab has for the first time demonstrated the link between ER quality control and development of neuronal ceroid lipofuscinoses (NCL), a group of inherited neurodegenerative lysosomal storage diseases. We have demonstrated that Cln variant proteins implicated in the disease undergo rapid proteasome-mediated degradation and complex with components of the ER extraction apparatus.
The provided data broadens our understanding of the molecular mechanism in the disposal of damaged or mutated ER proteins and provides a base for better understanding of the pathophysiology of NCL and associated diseases.