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Functional Roles for The Proteasome in Retro‐translocation of Polytopic Membrane Proteins for ERAD
Author(s) -
Smith Nathan James,
Adle David,
Lee Jaekwon
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.547.4
Subject(s) - endoplasmic reticulum associated protein degradation , proteasome , endoplasmic reticulum , microbiology and biotechnology , subcellular localization , ubiquitin ligase , ubiquitin , degron , chemistry , cytosol , atpase , cytoplasm , protein degradation , biology , biochemistry , unfolded protein response , enzyme , gene
The endoplasmic reticulum‐associated degradation (ERAD) system, known for its role in quality control of secretory proteins, is responsible for regulating Pca1, a cadmium‐extruding P‐type ATPase that plays a major role for cadmium detoxification in yeast Saccharomyces cerevisiae. Pca1 contains an N‐terminal, cadmium responsive degron, which targets it for degradation in the absence of cadmium to the proteasome. The mechanism by which the integral membrane protein Pca1 is removed from the ER for degradation by the cytoplasmic proteasome is unknown. Here we define the roles for the molecular factors involved in ERAD in dislodging Pca1 from the ER membrane. Pca1 is stabilized in cells lacking Doa10 E3 ligase and Ccd48 AAA‐type ATPase activity in ERAD. Unexpectedly, inhibition of proteasome activities results in accumulation of full‐length Pca1 in the ER membrane with no significant detection in the cytosol, indicating a role for the proteasome in efficient removal of Pca1 from the membrane. Experiments also display a physical interaction between the proteasome and Pca1 in an ubiqutinylation dependent manner. Analysis of another membrane bound ERAD substrate, STE6*, displays a similar phenomenon. Support provided by NIH 5RO1ES016337