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Content archived on 2024-05-29

Unfolded protein response in mammals


The eukaryotic unfolded protein response (UPR) is an integrated cellular stress response that detects incorrectly folded proteins at the endoplasmic reticulum and acts to minimize their accumulation. The proteasomal degradation of misfolded proteins by ER associated degradation (ERAD) is a central component of the response, involving ubiquitin-conjugating enzymes (Ubc's) and ubiquitin-protein ligases (E3's) that are specifically active at the ER membrane. Ubc6e is a novel ubiquitin-con jugating enzyme that lacks a homologue in yeast and is involved in ERAD of higher eukaryotes. It would be expected to have a role in minimizing the accumulation of misfolded proteins at the ER but its expression, regulation and involvement in degenerative diseases have not been well characterized. Our preliminary studies indicate that human Ubc6e is an extremely unstable target for degradation at the ER.

This degradation is mediated by the proteasome and is dependent in part on the catalytic activity of the enzyme itself. We conclude that Ubc6e is both a component and substrate for the mammalian ERAD pathway. The studies described in this proposal aim to identify the cis- and trans- regulatory factors involved in this degradation. We will determine the cellular conditions during which phosphorylation and stabilization of the enzyme are regulated, and address the implications of enzyme stabilization on ERAD functional output. Finally, we will assess the functional implications of proteolytic cleavage of Ubc6e at the ER membrane and subsequent localization to presumptive lysosomes. We will establish whether this reflects a novel mechanism for recruiting the degradative power of lysosomes to assist in the unfolded protein response specifically in higher eukaryotes.

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Av. Prof. Egas Moniz

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