XBP1-KLF9 Axis Acts as a Molecular Rheostat to Control the Transition from Adaptive to Cytotoxic Unfolded Protein Response

Fink, Emily E.; Moparthy, Sudha; Bagati, Archis; Bianchi‐Smiraglia, Anna; Lipchick, Brittany C.; Wolff, Dennis W.; Roll, Matthew V.; Wang, Jianmin; Liu, Song; Bakin, Andrei V.; Kandel, Eugene; Lee, Ann–Hwee; Nikiforov, Mikhail A.

doi:10.1016/j.celrep.2018.09.013

Cited by 45 publications

(43 citation statements)

References 33 publications

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“…Firstly, it was shown that overexpression of XBP1s induced apoptosis in human umbilical endothelial cells [99]. Secondly, a recent report showed that while XBP1 mediated adaptive signals at noncytotoxic, low levels of ER stress, it could mediate proapoptotic effects via upregulating the expression of the transcription factor KLF9 at cytotoxic, high levels of ER stress in WI38 human fibroblasts [100]. Although the effect of XBP1 depletion on ER stress-induced cell death was not examined in the latter report, these studies and ours together suggest that the IRE1-XBP1 axis provides pro-death signals under high-level ER stress conditions and that this may contribute to ER stress-induced cell death in several different cell types.…”

Section: Discussionmentioning

confidence: 99%

Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components

et al. 2020

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Background: Cell death triggered by unmitigated endoplasmic reticulum (ER) stress plays an important role in physiology and disease, but the death-inducing signaling mechanisms are incompletely understood. To gain more insight into these mechanisms, the ER stressor thapsigargin (Tg) is an instrumental experimental tool. Additionally, Tg forms the basis for analog prodrugs designed for cell killing in targeted cancer therapy. Tg induces apoptosis via the unfolded protein response (UPR), but how apoptosis is initiated, and how individual effects of the various UPR components are integrated, is unclear. Furthermore, the role of autophagy and autophagy-related (ATG) proteins remains elusive.Methods: To systematically address these key questions, we analyzed the effects of Tg and therapeutically relevant Tg analogs in two human cancer cell lines of different origin (LNCaP prostate-and HCT116 colon cancer cells), using RNAi and inhibitory drugs to target death receptors, UPR components and ATG proteins, in combination with measurements of cell death by fluorescence imaging and propidium iodide staining, as well as real-time RT-PCR and western blotting to monitor caspase activity, expression of ATG proteins, UPR components, and downstream ER stress signaling.Results: In both cell lines, Tg-induced cell death depended on death receptor 5 and caspase-8. Optimal cytotoxicity involved a non-autophagic function of MAP1LC3B upstream of procaspase-8 cleavage. PERK, ATF4 and CHOP were required for Tg-induced cell death, but surprisingly acted in parallel rather than as a linear pathway; ATF4 and CHOP were independently required for Tg-mediated upregulation of death receptor 5 and MAP1LC3B proteins, whereas PERK acted via other pathways. Interestingly, IRE1 contributed to Tg-induced cell death in a cell typespecific manner. This was linked to an XBP1-dependent activation of c-Jun N-terminal kinase, which was proapoptotic in LNCaP but not HCT116 cells. Molecular requirements for cell death induction by therapy-relevant Tg analogs were identical to those observed with Tg. Conclusions: Together, our results provide a new, integrated understanding of UPR signaling mechanisms and downstream mediators that induce cell death upon Tg-triggered, unmitigated ER stress.

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Section: Discussionmentioning

confidence: 99%

Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components

et al. 2020

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“…Activated IRE1α splices XBP1 mRNA, which encodes transcription factor to increase the protein-folding capacity and degrade misfolded proteins. While IRE1α engages STAT3 pathway to promote liver regeneration upon liver injury 26 , XBP1 switches prosurvival to proapoptotic signal cascades through multiple gene regulation 27,28 . It has been reported that ATF6 exerts a pro-inflammatory effect on ischemiareperfusion liver injury 29 .…”

Section: Discussionmentioning

confidence: 99%

Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver

Wang

Zhao

et al. 2020

Cell Death Dis

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Endoplasmic reticulum (ER) stress-associated cell death is prevalent in various liver diseases. However, the determinant mechanism how hepatocytes survive unresolved stress was still unclear. Interleukin-24 (IL-24) was previously found to promote ER stress-mediated cell death, and yet its expression and function in the liver remained elusive. Here we identified an antiapoptotic role of IL-24, which transiently accumulated within ER-stressed hepatocytes in a X-box binding protein 1 (XBP1)-dependent manner. Disruption of IL-24 increased cell death in the CCL 4-or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2α (eIF2α) or genetical ablation of C/EBP homologous protein (CHOP) restored hepatocyte function in the absence of IL-24. In a clinical setting, patients with acute liver failure manifested a profound decrease of hepatic IL-24 expression, which was associated with disease progression. In conclusion, intrinsic hepatocyte IL-24 maintains ER homeostasis by restricting the eIF2α-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.

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“…KLF9 can be induced by several physiological or pathological stresses. Current experimental evidence indicates that KLF9 plays a key hormone-dependent role in liver gluconeogenesis (9). Notably, a recent study indicated that KLF9 is induced by NF-E2-like basic leucine zipper transcriptional activator (Nrf2), thereby promoting cell oxidative stress (7).…”

Section: Introductionmentioning

confidence: 99%

Dexamethasone induces aberrant macrophage immune function and apoptosis

Zhao

et al. 2019

Oncol Rep

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Glucocorticoids (GCs) are known potent clinical drugs, however, their mode of action is still complex and debatable. Macrophages are the most important target of GCs and play a key role in tumor immunity in vivo, but their relationship is also controversial. In the present study, the lentivirus system was used to overexpress and knock down the level of transcription factor Krüppel-like factor 9 (KLF9). The results revealed that dexamethasone (Dex) induced ROS generation and mitochondria-dependent apoptosis in RAW 264.7 cells via the KLF9. In addition, overexpression of KLF9 significantly increased apoptosis of RAW 264.7 cells. Notably, ELISA assay revealed that increased expression of KLF9 inhibited LPS-induced COX-2 expression and reduced COX-2-derived prostaglandin E2 and pro-inflammatory cytokine secretion. Furthermore, a co-culture system was used to reveal that overexpression of KLF9 in RAW 264.7 cells promoted HepG2 cell survival. In summary, it is reported that KLF9 promoted apoptosis of proinflammatory macrophages, and suppressed the antitumor effects, which can be selectively targeted by GCs as a novel mechanism to suppress antineoplastic activity.

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XBP1-KLF9 Axis Acts as a Molecular Rheostat to Control the Transition from Adaptive to Cytotoxic Unfolded Protein Response

Cited by 45 publications

References 33 publications

Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components

Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components

Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver

Dexamethasone induces aberrant macrophage immune function and apoptosis

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