総合生命科学部 バイオフォーラム2017開催(2018年3月20日)

タンパク質動態研究所セミナー/第179回細胞生物学セミナー

日時 2018年3月20日(火)15:15開場
【第1部】15:30~16:30【第2部】16:30~17:30
場所 京都産業大学 15号館1階15102セミナー室
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備考 事前申込不要・入場無料
本講演は英語講演となります。通訳はありませんので、ご注意ください。

第1部:Dr. Jeffrey L. Brodsky(University of Pittsburgh, USA)

「Endoplasmic Reticulum Associated Degradation, Substrate Selection, and Protein Conformational Disorders」

Numerous proteins that play critical roles in cellular physiology transit through the secretory pathway. In fact, approximately one-third of all proteins in eukaryotes enter the secretory pathway via the endoplasmic reticulum (ER) prior to their delivery to other cellular compartments or prior to being secreted. Although most of these proteins fold efficiently, a significant percentage folds slowly or inefficiently, particularly when cells are stressed. Because unfolded proteins can aggregate and compromise cellular homeostasis—and in some cases trigger apoptosis—it is critical that aberrant proteins in the secretory pathway are recognized and then destroyed. Once selected by chaperones and chaperone-like lectins, ER proteins can be removed via a process we termed ER associated degradation (ERAD). During ERAD, defective polypeptides are delivered from the ER to the cytoplasm, are ubiquitinated at the ER membrane, and are destroyed by the proteasome. Many of the critical players in the ERAD pathway have been identified and their functions discerned. However, a growing number of substrate-specific modifiers of ERAD have also been identified. Moreover, some misfolded proteins escape the ERAD pathway but are selected for lysosome-mediated degradation. Because the ERAD pathway is associated with>70 diseases, we propose that ERAD modifiers might, in turn, be disease modifiers. We also propose that the correction of misfolded, disease-linked secreted proteins will require ERAD-targeted drugs. Therefore, we have used yeast-based expression systems to dissect the ERAD pathway for proteins linked to human diseases and to identify previously uncharacterized factors and pathways that modulate ERAD. Candidates from these efforts are then tested in mammalian cell models. In parallel, we identified small molecule modulators of ERAD and examined these in combination with clinical protein folding correctors. These studies are complemented by in vitro assays that dissect at which step in the ERAD pathway specific factors and small molecules act.

第2部:Dr. Gerardo Z. Lederkremer(Tel Aviv University, Israel)

「Timing of glycoprotein folding quality control: too slow or too fast?」

Current models suggest general slow trimming of mannose residues from glycoprotein N-glycans during their folding in the ER. If proper folding is accomplished in a timely manner the glycoprotein exits the ER to the Golgi and its final destination. If not, extensive trimming of 3 or all 4 alpha1,2 mannose residues targets mammalian unfolded or misfolded glycoproteins to endoplasmic reticulum-associated degradation (ERAD). The trimming precludes re-addition of a glucose residue and thus removes the glycoprotein molecule from the calnexin folding cycle. In addition, the trimming allows binding to the lectins OS-9 and XTP3-B that target the glycoprotein to ERAD. The timing of the mannose trimming process is crucial for glycoprotein quality control, as it determines ultimate fate between productive folding or degradation. The trimming is accomplished by ER mannosidase I (ERManI) with the help of the EDEMs. Recently, we also showed involvement of Mannosidase IA, previously thought to reside in the Golgi. We have determined that the slow mannose trimming is achieved by a process of compartmentalization, in which the mannosidases are located most of the time in specialized quality control vesicles (QCVs), segregated from their glycoprotein substrates. Concerning the EDEMs, although it was shown that their overexpression or depletion affects the trimming of mannose residues, whether they are truly mannosidases can only be established in vitro. I will present new data showing EDEM1 mannosidase activity in vitro. For both ERManI and EDEM1, the in vitro activity was highly dependent on an unfolded status of the glycoprotein substrate. Therefore, misfolded or unfolded glycoproteins are subject to differentially faster trimming (and consequent targeting to ERAD) than well-folded ones.
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