Intricately Regulated: A Cellular Toolbox for Fine-Tuning XBP1 Expression and Activity

Byrd, Andrew E.; Brewer, Joseph W.

doi:10.3390/cells1040738

Cited by 23 publications

(16 citation statements)

References 65 publications

(133 reference statements)

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“…One of the known fine-tuning mechanisms involves Xbp1 u protein resulting from unspliced XBP1 mRNA, which functions as a negative regulator of Xbp1 s that results from spliced XBP1 mRNA. This negative effect of Xbp1 u on Xbp1 s is thought to delimit the threshold of UPR activation and thereby confers a switch-like behavior upon UPR (Byrd and Brewer, 2012). We show that a similar regulation also exists in lower eukaryotes (A) Filamentous growth is triggered by bE/bW-dependent induction of rbf1 expression.…”

Section: Discussionmentioning

confidence: 68%

Crosstalk between the Unfolded Protein Response and Pathways That Regulate Pathogenic Development inUstilago maydis

et al. 2013

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The unfolded protein response (UPR) is a conserved eukaryotic signaling pathway regulating endoplasmic reticulum (ER) homeostasis during ER stress, which results, for example, from an increased demand for protein secretion. Here, we characterize the homologs of the central UPR regulatory proteins Hac1 (for Homologous to ATF/CREB1) and Inositol Requiring Enzyme1 in the plant pathogenic fungus Ustilago maydis and demonstrate that the UPR is tightly interlinked with the b mating-type-dependent signaling pathway that regulates pathogenic development. Exact timing of UPR is required for virulence, since premature activation interferes with the b-dependent switch from budding to filamentous growth. In addition, we found crosstalk between UPR and the b target Clampless1 (Clp1), which is essential for cell cycle release and proliferation in planta. The unusual C-terminal extension of the U. maydis Hac1 homolog, Cib1 (for Clp1 interacting bZIP1), mediates direct interaction with Clp1. The interaction between Clp1 and Cib1 promotes stabilization of Clp1, resulting in enhanced ER stress tolerance that prevents deleterious UPR hyperactivation. Thus, the interaction between Cib1 and Clp1 constitutes a checkpoint to time developmental progression and increased secretion of effector proteins at the onset of biotrophic development. Crosstalk between UPR and the b mating-type regulated developmental program adapts ER homeostasis to the changing demands during biotrophy.

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Section: Discussionmentioning

confidence: 68%

Crosstalk between the Unfolded Protein Response and Pathways That Regulate Pathogenic Development inUstilago maydis

et al. 2013

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“…Similar results were observed in HFA as shown in Figure 5D, where increase in spliced XBP1 was observed at 6 H. However, the protein lysates obtained from mouse brains did not show XBP1 splicing (Figure 6). The discrepancy between the levels of XBP1s observed at protein and RNA levels could be explained by possible role of post-translational modification of XBP1 protein [61]. As demonstrated by Yoshida et al, XBP1U forms a heterodimer with XBP1S during prolonged UPR and decreases its activity.…”

Section: Discussionmentioning

confidence: 99%

Methamphetamine-mediated endoplasmic reticulum (ER) stress induces type-1 programmed cell death in astrocytes via ATF6, IRE1α and PERK pathways

Shah

Kumar

2016

Oncotarget

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Methamphetamine (MA), a psychostimulant drug has been associated with a variety of neurotoxic effects which are thought to be mediated by induction of pro-inflammatory cytokines/chemokines, oxidative stress and damage to blood-brain-barrier. Conversely, the ER stress-mediated apoptosis has been implicated in several neurodegenerative diseases. However, its involvement in MA-mediated neurodegenerative effects remains largely unexplored. The present study was undertaken to assess the effect of MA on ER stress and its possible involvement in apoptosis. For this purpose, SVGA astrocytes were treated with MA, which induced the expressions of BiP and CHOP at both, mRNA and protein levels. This phenomenon was also confirmed in HFA and various regions of mouse brain. Assessment of IRE1α, ATF6 and PERK pathways further elucidated the mechanistic details underlying MA-mediated ER stress. Knockdown of various intermediate molecules in ER stress pathways using siRNA demonstrated reduction in MA-mediated CHOP. Finally, MA-mediated apoptosis was demonstrated via MTT assay and TUNEL staining. The involvement of ER stress in the apoptosis was demonstrated with the help of MTT and TUNEL assays in the presence of siRNA against various ER stress proteins. The apoptosis also involved activation of caspase-3 and caspase-9, which was reversed by knockdown with various siRNAs. Altogether, this is the first report demonstrating mechanistic details responsible for MA-mediated ER stress and its role in apoptosis. This study provides a novel group of targets that can be explored in future for management of MA-mediated cell death and MA-associated neurodegenerative disorders.

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“…Importantly, the non-spliced Xbp1 mRNA encodes the protein XBP1u (XBP1 unspliced), which is an inactive form with no transcriptional activity because it lacks the transactivating domain, and is an extremely short-lived protein. Interestingly, however, XBP1u was also found to interact with XBP1s under ER stress conditions, functioning as a negative feedback regulator [ 72 , 73 ].…”

Section: The Unfolded Protein Responsementioning

confidence: 99%

ER Stress and Unfolded Protein Response in Leukemia: Friend, Foe, or Both?

et al. 2021

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The unfolded protein response (UPR) is an evolutionarily conserved adaptive signaling pathway triggered by a stress of the endoplasmic reticulum (ER) lumen compartment, which is initiated by the accumulation of unfolded proteins. This response, mediated by three sensors-Inositol Requiring Enzyme 1 (IRE1), Activating Transcription Factor 6 (ATF6), and Protein Kinase RNA-Like Endoplasmic Reticulum Kinase (PERK)—allows restoring protein homeostasis and maintaining cell survival. UPR represents a major cytoprotective signaling network for cancer cells, which frequently experience disturbed proteostasis owing to their rapid proliferation in an usually unfavorable microenvironment. Increased basal UPR also participates in the resistance of tumor cells against chemotherapy. UPR activation also occurs during hematopoiesis, and growing evidence supports the critical cytoprotective role played by ER stress in the emergence and proliferation of leukemic cells. In case of severe or prolonged stress, pro-survival UPR may however evolve into a cell death program called terminal UPR. Interestingly, a large number of studies have revealed that the induction of proapoptotic UPR can also strongly contribute to the sensitization of leukemic cells to chemotherapy. Here, we review the current knowledge on the consequences of the deregulation of UPR signaling in leukemias and their implications for the treatment of these diseases.

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Intricately Regulated: A Cellular Toolbox for Fine-Tuning XBP1 Expression and Activity

Cited by 23 publications

References 65 publications

Crosstalk between the Unfolded Protein Response and Pathways That Regulate Pathogenic Development inUstilago maydis

Crosstalk between the Unfolded Protein Response and Pathways That Regulate Pathogenic Development inUstilago maydis

Methamphetamine-mediated endoplasmic reticulum (ER) stress induces type-1 programmed cell death in astrocytes via ATF6, IRE1α and PERK pathways

ER Stress and Unfolded Protein Response in Leukemia: Friend, Foe, or Both?

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