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Co‐ and Post‐Translational Protein Folding and Degradation at the ER Membrane
Author(s) -
Brodsky Jeffrey L
Publication year - 2006
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.20.5.a1473-e
Subject(s) - endoplasmic reticulum associated protein degradation , endoplasmic reticulum , chaperone (clinical) , cystic fibrosis transmembrane conductance regulator , microbiology and biotechnology , proteasome , biology , biogenesis , unfolded protein response , proteostasis , protein degradation , protein folding , transmembrane protein , ubiquitin , proteome , biochemistry , gene , medicine , receptor , pathology
It is becoming increasingly clear that a significant percentage of newly synthesized secreted proteins are degraded either during or soon after their synthesis in eukaryotes. What is less clear is how these substrates are recognized by the endoplasmic reticulum (ER) quality control machinery and then targeted for proteasome‐mediated degradation. Such an undertaking is vital as many substrates of the ER associated degradation (ERAD) pathway impact the onset of specific human diseases. To better define the molecular basis of substrate selection and delivery to the proteasome, we have developed yeast expression systems for 5 human proteins whose functions are relevant to disease states. This pursuit makes available the use of yeast proteomic and genomic tools to identify modulators of protein quality control in humans. For example, we established a yeast expression system for the cystic fibrosis transmembrane conductance regulator (CFTR), the protein that when mutated causes cystic fibrosis, and showed that Hsp70 and Hsp90 molecular chaperones differentially affect CFTR biogenesis. More recent transcriptional profiling analyses between CFTR‐expressing and control cells indicate that small heat shock proteins (sHsps) are induced upon CFTR expression. Deletion of the corresponding genes in yeast significantly slows CFTR degradation whereas over‐expression of a conserved sHsp in mammalian cells stabilizes only the disease‐causing CFTR mutant. These data indicate that sHsps represent another class of chaperones that play an important role in ERAD and suggest the value of further developing yeast expression systems. Combined with in vitro assays that recapitulate substrate polyubiquitination, we hope to uncover how sHsps and other factors modulate protein biogenesis in the early secretory pathway of eukaryotes.