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PMID: 19073890 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Analysis of quality control substrates in distinct cellular compartments reveals a unique role for Rpn4p in tolerating misfolded membrane proteins.

Molecular biology of the cell ·Vol. 20 ·No. 3 ·2009-02-00 ·Pages 1006-19

Metzger MB, Michaelis S

Abstract

ER quality control (ERQC) prevents the exit of misfolded secretory and membrane proteins from the ER. A critical aspect of ERQC is a transcriptional response called the unfolded protein response (UPR), which up-regulates genes that enable cells to cope with misfolded, ER-retained proteins. In this study, we compare the transcriptional responses in yeast resulting from the acute expression of misfolded proteins residing in three different cellular compartments (the ER lumen, membrane, and cytosol), and find that each elicits a distinct transcriptional response. The classical UPR response, here-designated UPR-L, is induced by the ER lumenal misfolded protein, CPY*. The UPR-Cyto response is induced by the cytosolic protein, VHL-L158P, and is characterized by a rapid, transient induction of cytosolic chaperones similar to the heat-shock response. In contrast, the misfolded membrane protein with a cystolic lesion, Ste6p*, elicits a unique response designated UPR-M/C, characterized by the modest induction of >20 genes regulated by Rpn4p, an activator of proteasomal genes. Independently, we identified several genes required for yeast viability during UPR-M/C stress, but not UPR-L or UPR-Cyto stress. Among these is RPN4, highlighting the importance of the Rpn4p-dependent response in tolerating UPR-M/C stress. Further analysis suggests the requirement for Rpn4p reflects severe impairment of the proteasome by UPR-M/C stress.

MeSH Terms
Blotting, Northern Cell Compartmentation Cytosol/metabolism DNA-Binding Proteins/metabolism Gene Expression Regulation, Fungal Genes, Fungal Membrane Proteins/chemistry,metabolism Microbial Viability Models, Biological Molecular Chaperones/genetics Oligonucleotide Array Sequence Analysis Proteasome Endopeptidase Complex/metabolism Protein Folding Saccharomyces cerevisiae/cytology,genetics,metabolism Saccharomyces cerevisiae Proteins/metabolism Stress, Physiological Substrate Specificity Transcription Factors/metabolism Transcription, Genetic Ubiquitin/metabolism
Chemicals
DNA-Binding Proteins Membrane Proteins Molecular Chaperones RPN4 protein, S cerevisiae Saccharomyces cerevisiae Proteins Transcription Factors Ubiquitin Proteasome Endopeptidase Complex
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Metzger Meredith Boyle
Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Michaelis Susan
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1939-4586
DOI
10.1091/mbc.e08-02-0140
Published
2009-02-00
Epub
2008-00-10
Pages
1006-19
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC2633399
Subset
IM
Grants
NIGMS NIH HHS · R01 GM051508 · United States
NIGMS NIH HHS · GM51508 · United States
External Links
PubMed source DOI: 10.1091/mbc.e08-02-0140 PMC Full Text View journal details
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