Review
Modulating stress responses by the UPRosome: A matter of life and death

https://doi.org/10.1016/j.tibs.2011.03.001Get rights and content

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR) through the activation of specialized sensors including inositol-requiring enzyme-1α (IRE1α). IRE1α signals by assembling a dynamic protein platform referred to as the UPRosome, where different modulator and adaptor proteins assemble to regulate the kinetics and amplitude of UPR effector responses. Conversely, chronic ER stress can cause apoptosis. Recent evidence indicates that several apoptosis-related proteins interact with IRE1α, regulating its prosurvival activities and performing a dual function in the regulation of cell death and adaptation to stress. Based on the increasing relevance of ER stress to the occurrence of diverse pathological conditions, strategies to target and modulate the assembly and composition of the UPRosome could have therapeutic benefits for disease intervention.

Section snippets

ER stress and cell fate decisions

Studying the processes underlying the folding of proteins in the endoplasmic reticulum (ER) has become a focus of research to understand the cause of many diseases including neurodegenerative disorders, cancer and diabetes [1]. The ER facilitates protein folding and secretion, in addition to modulating protein quality control mechanisms. The fidelity of protein synthesis in the secretory pathway is controlled by various processes along the different steps of protein synthesis, maturation and

UPR activation and stress sensors

The accumulation of unfolded proteins in the ER of mammalian cells is presumed to be directly or indirectly detected by at least three ER-resident UPR stress sensors: (i) inositol-requiring enzyme 1α (IRE1α); (ii) protein kinase RNA-activated (PKR)-like ER kinase (PERK); and (iii) activating transcription factor 6 (ATF6) [2]. Each of these sensors relays information about the protein folding status in the ER lumen to the nucleus, thereby controlling the expression of selected transcription

UPR activation, stress adaptation and apoptosis: a matter of time

Activation of UPR sensors theoretically triggers four waves of responses over time to restore protein folding homeostasis in the ER and then shift adaptive programs toward the induction of apoptosis to eliminate irreversibly damaged cells (Figure 1 and Box 2): (i) an immediate response to decrease the load of unfolded proteins in the ER; (ii) a transcriptional reaction controlling the upregulation of UPR target genes related to folding and quality control; (iii) a transition phase; and (iv) an

The UPRosome: dynamic modulation of IRE1α signaling

Accumulating evidence indicates that the amplitude and duration of IRE1α signaling is controlled by the assembly of a protein platform referred to as the UPRosome [3] (Table 1 and Figure 2b). In this regulatory pathway, an interesting crosstalk is observed between the apoptotic and the UPR machinery, given the bifunctional roles of these proteins in the UPR and downstream in apoptosis signaling (reviewed in [52], Table 1). Some examples suggest that the association of several of these

The IRE1α UPRosome in human disease

Although ER stress is observed in a variety of disorders, the actual contribution of the pathway to disease progression has been established in only a few cases; most available data are either correlative or based on in vitro evidence 1, 5. ER stress responses are commonly associated with many diseases related to the accumulation of intracellular and/or extracellular abnormal aggregates containing specific misfolded proteins. Persistent ER stress might contribute to the development of numerous

Concluding remarks

In this review, we have discussed accumulating evidence that indicates a tight regulation of the UPR through the assembly of dynamic interactomes. Fine-tuning of the UPR is predicted to be fundamental in cell fate decisions by determining adaptation and survival to ER stress or the elimination of irreversibly damaged cells. The recognition of the importance of ER stress-induced cell death has increased significantly in recent years. As a specialized organelle of protein folding and secretion,

Acknowledgments

This research was supported by FONDECYT (Fondo nacional de desarrollo Cientifico y Tecnologico) no. 1100176, Millennium Nucleus no. P07-048-F, FONDAP (Fund for Advanced Research in Priority Areas) grant no. 15010006, Michael J. Fox Foundation for Parkinson's Research, ICGEB, Genzyme, Alzheimer's Disease Foundation, and CHDI Foundation Inc. (to C.H.) and FONDECYT no. 3110067 (U.W.).

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      Citation Excerpt :

      The UPR restores ER homeostasis by decreasing protein synthesis or increasing the expression of genes that encode chaperones related to protein folding, chaperones related to posttranslational modification and enzymes related to protein processing, and residual misfolded proteins are degraded by the proteasome via the ER-related degradation (ERAD) process (Adachi et al., 2008; Fonseca et al., 2011; Smith et al., 2011; Walter et al., 2011; Chang et al., 2018; Xu et al., 2020). When these mechanisms cannot alleviate ER stress, the UPR initiates apoptosis or autophagy (Merksamer et al., 2010; Woehlbier et al., 2011; Hetz., 2012; Jäger et al., 2012; Wang et al., 2018; Li et al., 2019). ER stress participates in the pathogenesis of many diseases, such as obesity (Lebeaupin et al., 2018), diabetes (Back et al., 2012), cancers (Cubillos-Ruiz et al., 2017), neurodegenerative diseases (Cai et al., 2016), and inflammatory and autoimmune diseases (Bettigole et al., 2015; Wang et al., 2019).

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