Stress-Independent Activation of XBP1s and/or ATF6 Reveals Three Functionally Diverse ER Proteostasis Environments

Citations Over TimeTop 1% of 2013 papers

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.

Related Papers

• → QUANTITATIVE MEASUREMENT OF SPLICED XBP1 mRNA AS AN INDICATOR OF ENDOPLASMIC RETICULUM STRESS(2006)112 cited
• → The specialized unfolded protein response of B lymphocytes: ATF6α-independent development of antibody-secreting B cells(2012)53 cited
• → PERK regulated miR-424(322)-503 cluster fine-tunes activation of IRE1 and ATF6 during Unfolded Protein Response(2015)43 cited
• → Endoplasmic reticulum stress and unfolded protein response are involved in paediatric inflammatory bowel disease(2014)34 cited
• → A decay of the adaptive capacity of the unfolded protein response exacerbates Alzheimer's disease(2017)13 cited