Targeting the unfolded protein response for disease intervention

Abstract

Therapeutic strategies directed to regulate the activity of different UPR signaling arms may reduce stress levels with a therapeutic gain. Recent drug discovery efforts have identified small molecules that target specific UPR components, providing protection on various disease models. However, important side effects are predicted in the chronic administration due to the fundamental role of the UPR in highly secretory organs such as liver and pancreas. To overcome these problems, we propose the use of combinatorial treatments of selected drugs with natural compounds that are known to modulate the ER proteostasis network.

Uromodulin p.Cys147Trp mutation drives kidney disease by activating ER stress and apoptosis

“…Efforts are currently underway to identify mTOR-independent mechanisms to enhance autophagy (92,93). In addition to strategies that inhibit downstream cell death mediators like TNF-α or activate endogenous autophagy programs to alleviate the cellular burden of misfolded protein accumulation, an emergent therapeutic approach to treating chronic states of ER stress and UPR activation, particularly in the field of neurodegeneration (94,95), has yielded several small-molecule modulators of components of the UPR itself. In particular, compounds such as GSK2606414 and ISRIB act at different levels of the PERK/eIF2α axis to inhibit the UPR and have proven effective in murine models of neurodegeneration (96)(97)(98).…”

Oxidative and endoplasmic reticulum stress in respiratory disease

“…Although some protein misfolding occurs in all cells and increases with increasing protein complexity, when an excess of unfolded protein is present, or when intracellular Ca 2+ levels are disturbed, the unfolded protein response (UPR) is triggered. The UPR involves a series of signalling and transcriptional events to restore ER homeostasis via decreased translation, upregulation of ER chaperones and other molecules associated with productive folding (ER‐associated folding or ERAF), and increased degradation of misfolded proteins (ER‐associated degradation or ERAD), and this has been extensively reviewed 3, 4, 5. Briefly, there are three major arms of the UPR regulated by (1) the ER resident protein kinase RNA‐like ER kinase (PERK) which suppresses translation via eIF2α and includes transcriptional responses via activating transcription factor‐4 (ATF4) and CCAAT/enhancer‐binding protein homologous protein (CHOP), which can lead to ER stress‐induced apoptosis; (2) the endoribonucleases inositol requiring enzyme 1 (IRE1α) (ubiquitously expressed) and IRE1β (confined to mucosal secretory cells including in the lung), which splice the X‐box‐binding protein (XBP1) mRNA leading to translation of the sXBP1 transcription factor that drives expression of chaperones and other ER resident proteins required for folding and ERAD; and (3) the transcription factor ATF6, which also promotes production of proteins enhancing ER function.…”

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

“…Even less is known about the interactions of cytosolic bacteria with the ER and UPR. As ER stress and the UPR also contribute to the development of other health disorders, including cancer, diabetes, and inflammatory diseases and have been therapeutically targeted in some of these contexts (17)(18)(19)(20)(21)(22)(23)(24)(25), dissecting the interplay between microbes, the ER, and the UPR is a burgeoning area of microbial pathogenesis research that could ultimately have an impact that extends beyond infectious disease.…”