The unfolded protein response supports cellular robustness as a broad-spectrum compensatory pathway

Abstract

Stress pathways monitor intracellular systems and deploy a range of regulatory mechanisms in response to stress. One of the bestcharacterized pathways, the unfolded protein response (UPR), is responsible for maintaining endoplasmic reticulum (ER) homeostasis. The highly conserved Ire1 branch regulates hundreds of gene targets by activating a UPR-specific transcription factor. To understand how the UPR manages ER stress, a unique genetic approach was applied to reveal how the system corrects disequilibria. The data show that the UPR can address a wide range of dysfunctions that are otherwise lethal if not for its intervention. Transcriptional profiling of stressalleviated cells shows that the program can be modulated, not just in signal amplitude, but also through differential target gene expression depending on the stress. The breadth of the functions mitigated by the UPR further supports its role as a major mechanism maintaining systems robustness.chaperones | signal transduction | protein folding | protein degradation | glycosylation

Limitation of individual folding resources in the ER leads to outcomes distinct from the unfolded protein response

“…Nonetheless, because the ER fulfils multiple additional functions, such as calcium homeostasis and lipid synthesis, different physiological conditions may require distinct outcomes, characterized by the upregulation of selective subsets of ER genes. Indeed, recent work in yeast shows that UPR signaling can cause differential target gene expression depending on the nature of the stress (Thibault et al, 2011).…”

A Bystander Mechanism Explains the Specific Phenotype of a Broadly Expressed Misfolded Protein

“…As expected for a folding mutation [60], altering the overall folding capacity of the ER modulated the penetrance of the dauer phenotype caused by the endogenous DAF-28(R37C) mutation, while the transgenic mutant protein accumulated in tissues and exhibited aggregation-like behavior. Interestingly, as judged by its uptake into coelomocytes, at least some of the DAF-28(R37C)::mCherry mutant protein was secreted.…”

HDAC Inhibitor Modulation of Proteotoxicity as a Therapeutic Approach in Cancer

“…Interestingly, IRE1 has been shown to interact directly with proapoptotic members of the BCL-2 family of apoptosis regulators (Hetz et al, 2006), and it also physically associates with apoptosis signaling kinase-1 via TRAF2 to promote activation of the proapoptotic Jun N-terminal kinase (JNK) kinase (Nishitoh et al, 2002). Nonetheless, recent studies have demonstrated that XBP1 controls the expression of hundreds of stress-responsive genes involved in cytoprotective responses that circumvent lethal cell injury (Thibault, Ismail, & Ng, 2011). Therefore, like the other arms of the UPR, IRE1-XBP1 signaling may serve a primarily cytoprotective role in cells exposed to ER stress.…”