Triazoloacridone C-1305 impairs XBP1 splicing by acting as a potential IRE1α endoribonuclease inhibitor

Bartoszewska, Sylwia; Króliczewski, Jarosław; Crossman, David K.; Pogorzelska, Aneta; Bagiński, Maciej; Collawn, James F.; Bartoszewski, Rafał

doi:10.1186/s11658-021-00255-y

Cited by 10 publications

(10 citation statements)

References 54 publications

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“…In the current study, we observed that genetic targeting of XBP1 is significantly more deleterious to cells with hyperactive AKT ( Figure 4 B). XBP1 production is potentially targetable through the chemical inhibition of IRE1α, and numerous compounds with such activity have been described [ 54 , 55 , 56 , 57 , 58 , 59 ]. However, IRE1α has been reported to carry out other important functions, such as housekeeping control of mitochondrial calcium uptake [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

Babagana

Brown

Slabodkin

et al. 2021

IJMS

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Hyperactivity of serine-threonine kinase AKT is one of the most common molecular abnormalities in cancer, where it contributes to poor outcomes by facilitating the growth and survival of malignant cells. Despite its well-documented anti-apoptotic effects, hyperactivity of AKT is also known to be stressful to a cell. In an attempt to better elucidate this phenomenon, we observed the signs of proteotoxic stress in cells that harbor hyperactive AKT or have lost its principal negative regulator, PTEN. The activity of HSF1 was predictably elevated under these circumstances. However, such cells proved more sensitive to various regimens of heat shock, including the conditions that were well-tolerated by syngeneic cells without AKT hyperactivity. The sensitizing effect of hyperactive AKT was also seen in HSF1-deficient cells, suggesting that the phenomenon does not require the regulation of HSF1 by this kinase. Notably, the elevated activity of AKT was accompanied by increased levels of XBP1, a key component of cell defense against proteotoxic stress. Interestingly, the cells harboring hyperactive AKT were also more dependent on XBP1 for their growth. Our observations suggest that proteotoxic stress conferred by hyperactive AKT represents a targetable vulnerability, which can be exploited by either elevating the stress above the level tolerated by such cells or by eliminating the factors that enable such tolerance.

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Section: Discussionmentioning

confidence: 99%

Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

Babagana

Brown

Slabodkin

et al. 2021

IJMS

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“…CTRL cells were treated with vehicle CTRL, DMSO (< 0.5% v/v; Sigma, D2650). Furthermore, to verify IRE1 activity, cells treated were 20 µM 4µ8C (an IRE1 inhibitor, Sigma-Aldrich, SML0949) dissolved in DMSO (Sigma-Aldrich, St. Louis, MI, USA) [ 35 ].…”

Section: Methodsmentioning

confidence: 99%

Genome-wide mRNA profiling identifies X-box-binding protein 1 (XBP1) as an IRE1 and PUMA repressor

Gebert

Sobolewska

Bartoszewska

et al. 2021

Cell. Mol. Life Sci.

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Accumulation of misfolded proteins in ER activates the unfolded protein response (UPR), a multifunctional signaling pathway that is important for cell survival. The UPR is regulated by three ER transmembrane sensors, one of which is inositol-requiring protein 1 (IRE1). IRE1 activates a transcription factor, X-box-binding protein 1 (XBP1), by removing a 26-base intron from XBP1 mRNA that generates spliced XBP1 mRNA (XBP1s). To search for XBP1 transcriptional targets, we utilized an XBP1s-inducible human cell line to limit XBP1 expression in a controlled manner. We also verified the identified XBP1-dependent genes with specific silencing of this transcription factor during pharmacological ER stress induction with both an N-linked glycosylation inhibitor (tunicamycin) and a non-competitive inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) (thapsigargin). We then compared those results to the XBP1s-induced cell line without pharmacological ER stress induction. Using next‐generation sequencing followed by bioinformatic analysis of XBP1-binding motifs, we defined an XBP1 regulatory network and identified XBP1 as a repressor of PUMA (a proapoptotic gene) and IRE1 mRNA expression during the UPR. Our results indicate impairing IRE1 activity during ER stress conditions accelerates cell death in ER-stressed cells, whereas elevating XBP1 expression during ER stress using an inducible cell line correlated with a clear prosurvival effect and reduced PUMA protein expression. Although further studies will be required to test the underlying molecular mechanisms involved in the relationship between these genes with XBP1, these studies identify a novel repressive role of XBP1 during the UPR.

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“…Proper ER functionality is essential for cells; however, various conditions can interfere with its operation, leading to a build up of proteins, referred to as ER stress [ 35 ]. Unfolded protein response (UPR) is caused by the build up of misfolded proteins in the ER, which is the classical signaling pathway for ER stress [ 36 , 37 ]. UPR might be activated by specific conditions including dithiothreitol (DTT), tunicamycin (Tm), and low concentrations of inositol [ 38 ].…”

Section: Functions Of Fitm Proteinsmentioning

confidence: 99%

Fat storage-inducing transmembrane proteins: beyond mediating lipid droplet formation

Wang

Chen

et al. 2022

Cell Mol Biol Lett

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Fat storage-inducing transmembrane proteins (FITMs) were initially identified in 2007 as members of a conserved endoplasmic reticulum (ER) resident transmembrane protein gene family, and were found to be involved in lipid droplet (LD) formation. Recently, several studies have further demonstrated that the ability of FITMs to directly bind to triglyceride and diacylglycerol, and the diphosphatase activity of hydrolyzing fatty acyl-CoA, might enable FITMs to maintain the formation of lipid droplets, engage in lipid metabolism, and protect against cellular stress. Based on the distribution of FITMs in tissues and their important roles in lipid droplet biology and lipid metabolism, it was discovered that FITMs were closely related to muscle development, adipocyte differentiation, and energy metabolism. Accordingly, the abnormal expression of FITMs was not only associated with type 2 diabetes and lipodystrophy, but also with cardiac disease and several types of cancer. This study reviews the structure, distribution, expression regulation, and functionality of FITMs and their potential relationships with various metabolic diseases, hoping to provide inspiration for fruitful research directions and applications of FITM proteins. Moreover, this review will provide an important theoretical basis for the application of FITMs in the diagnosis and treatment of related diseases.

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Triazoloacridone C-1305 impairs XBP1 splicing by acting as a potential IRE1α endoribonuclease inhibitor

Cited by 10 publications

References 54 publications

Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

Genome-wide mRNA profiling identifies X-box-binding protein 1 (XBP1) as an IRE1 and PUMA repressor

Fat storage-inducing transmembrane proteins: beyond mediating lipid droplet formation

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