Functional and Genomic Analyses Reveal an Essential Coordination between the Unfolded Protein Response and ER-Associated Degradation

Abstract

The unfolded protein response (UPR) regulates gene expression in response to stress in the endoplasmic reticulum (ER). We determined the transcriptional scope of the UPR using DNA microarrays. Rather than regulating only ER-resident chaperones and phospholipid biosynthesis, as anticipated from earlier work, the UPR affects multiple ER and secretory pathway functions. Studies of UPR targets engaged in ER-associated protein degradation (ERAD) reveal an intimate coordination between these responses: efficient ERAD requires an intact UPR, and UPR induction increases ERAD capacity. Conversely, loss of ERAD leads to constitutive UPR induction. Finally, simultaneous loss of ERAD and the UPR greatly decreases cell viability. Thus, the UPR and ERAD are dynamic responses required for the coordinated disposal of misfolded proteins even in the absence of acute stress.

Roles of CHOP/GADD153 in endoplasmic reticulum stress

“…10 In a later phase, components of ER-associated degradation (ERAD), including ER degradation-enhancing a-mannosidase-like protein (EDEM), are transcriptionally induced to eliminate misfolded proteins in the ER by the ubiquitin-proteasome system. [11][12][13] The third involves activation of NFkB, a transcription factor known as a mediator of immune and antiapoptotic responses. 14 This pathway is designated ER overload response (EOR), because it is triggered by accumulation of membrane proteins in the ER.…”

Approaches to imaging unfolded secretory protein stress in living cells

“…UPR activation triggers a transcriptional program that upregulates expression of ~400 genes in the S. cerevisiae [10]. Many features of the UPR are conserved in metazoans with additional components that increase the complexity of the stress response.…”

“…For example, yeast have one sensor/effector (Ire1) and metazoans have at least three (IRE1, PERK, and ATF6) ( Figure 1 ), with mammals also encoding two isoforms of IRE1 (α and β) and ATF6 (α and β) [8]. In S. cerevisiae , Ire1 cleaves HAC1 mRNA as part of a splicing reaction [9] to enable correct translation of the transcription factor Hac1 and upregulation of ~400 UPR target genes (Figure 1) [10]. Targets include ER chaperones, degradation machinery and genes involved in lipid synthesis [10].…”

“…In S. cerevisiae , Ire1 cleaves HAC1 mRNA as part of a splicing reaction [9] to enable correct translation of the transcription factor Hac1 and upregulation of ~400 UPR target genes (Figure 1) [10]. Targets include ER chaperones, degradation machinery and genes involved in lipid synthesis [10]. Attenuation of Ire1 signaling is critical for yeast cell adaptation to ER stress and Ire1 mutants unable to deactivate following UPR induction are hypersensitive to ER stressors [11, 12].…”

Measurement of the Unfolded Protein Response (UPR) in Monocytes

“…ERAD ensures the removal of terminally misfolded proteins from the ER lumen to the cytoplasm for ultimate degradation by the ubiquitin-proteasome system (Travers et al, 2000).…”