title: Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments.
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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Shoulders
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ryno
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Genereux
authors.forename: James J
authors.initials: JJ
authors.lastname: Moresco
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Tu
authors.forename: Chunlei
authors.initials: C
authors.lastname: Wu
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Su
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.forename: R Luke
authors.initials: RL
authors.lastname: Wiseman
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000633:toxicity; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D011228:Prealbumin / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects; D040901:Proteomics; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects; D014295:Trimethoprim / Q000494:pharmacology; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
chemical_list: D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D011228:Prealbumin; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D004317:Doxorubicin; D014295:Trimethoprim