title: Ubiquitin-dependent protein degradation at the yeast endoplasmic reticulum and nuclear envelope.
abstract: The endoplasmic reticulum (ER) is the primary organelle in eukaryotic cells where membrane and secreted proteins are inserted into or across cell membranes. Its membrane bilayer and luminal compartments provide a favorable environment for the folding and assembly of thousands of newly synthesized proteins. However, protein folding is intrinsically error-prone, and various stress conditions can further increase levels of protein misfolding and damage, particularly in the ER, which can lead to cellular dysfunction and disease. The ubiquitin-proteasome system (UPS) is responsible for the selective destruction of a vast array of protein substrates, either for protein quality control or to allow rapid changes in the levels of specific regulatory proteins. In this review, we will focus on the components and mechanisms of ER-associated protein degradation (ERAD), an important branch of the UPS. ER membranes extend from subcortical regions of the cell to the nuclear envelope, with its continuous outer and inner membranes; the nuclear envelope is a specialized subdomain of the ER. ERAD presents additional challenges to the UPS beyond those faced with soluble substrates of the cytoplasm and nucleus. These include recognition of sugar modifications that occur in the ER, retrotranslocation of proteins across the membrane bilayer, and transfer of substrates from the ER extraction machinery to the proteasome. Here, we review characteristics of ERAD substrate degradation signals (degrons), mechanisms underlying substrate recognition and processing by the ERAD machinery, and ideas on the still unresolved problem of how substrate proteins are moved across and extracted from the ER membrane.
authors.affiliation: Department of Molecular Biophysics & Biochemistry, Yale University , New Haven, CT , USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Zattas
authors.forename: Mark
authors.initials: M
authors.lastname: Hochstrasser
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination; D015003:Yeasts / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: Cdc48/p97; ER-associated degradation; proteasome; proteolysis; ubiquitination