Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments.
Cell Rep, 2013/4/25;3(4):1279-92.
Shoulders MD[1], Ryno LM, Genereux JC, Moresco JJ, Tu PG, Wu C, Yates JR 3rd, Su AI, Kelly JW, Wiseman RL
Affiliations
PMID: 23583182
Impact factor: 9.995
Abstract
The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis through the activation of transcription factors such as XBP1s and ATF6. The functional consequences of these transcription factors for ER proteostasis remain poorly defined. Here, we describe methodology that enables orthogonal, small-molecule-mediated activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the same cell independent of stress. We employ transcriptomics and quantitative proteomics to evaluate ER proteostasis network remodeling owing to the XBP1s and/or ATF6 transcriptional programs. Furthermore, we demonstrate that the three ER proteostasis environments accessible by activating XBP1s and/or ATF6 differentially influence the folding, trafficking, and degradation of destabilized ER client proteins without globally affecting the endogenous proteome. Our data reveal how the ER proteostasis network is remodeled by the XBP1s and/or ATF6 transcriptional programs at the molecular level and demonstrate the potential for selective restoration of aberrant ER proteostasis of pathologic, destabilized proteins through arm-selective UPR activation.
MeSH terms
Activating Transcription Factor 6; DNA-Binding Proteins; Doxorubicin; Endoplasmic Reticulum; HEK293 Cells; Hep G2 Cells; Humans; Prealbumin; Protein Folding; Proteomics; Regulatory Factor X Transcription Factors; Transcription Factors; Transcription, Genetic; Transcriptome; Trimethoprim; Unfolded Protein Response; X-Box Binding Protein 1
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