bims-unfpre 2022-10-16 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022–10–16
twelve papers selected by
Susan Logue, University of Manitoba

Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes.
The Role of the Hypoxia-Related Unfolded Protein Response (UPR) in the Tumor Microenvironment.
Bip-Yorkie interaction determines oncogenic and tumor-suppressive roles of Ire1/Xbp1s activation.
IRE1α-XBP1 regulates PDK1-dependent induction of epithelial-mesenchymal transition in non-small cell lung cancer cells.
Endoplasmic Reticulum Homeostasis Regulates TLR4 Expression and Signaling in Mast Cells.
A possible connection between reactive oxygen species and the unfolded protein response in lens development: From insight to foresight.
Editorial: Unfolded protein response (UPR): An impending target for multiple neurological disorders.
Mitoregulin controls mitochondrial function and stress-adaptation response during early phase of endoplasmic reticulum stress in breast cancer cells.
Mitochondrial Unfolded Protein Response in Ischemia-Reperfusion Injury.
Knockdown of TMEM160 leads to an increase in reactive oxygen species generation and the induction of the mitochondrial unfolded protein response.
KIRA8 attenuates non-alcoholic steatohepatitis through inhibition of the IRE1α/XBP1 signalling pathway.
Inhibition of mitochondrial respiration has fundamentally different effects on proliferation, cell survival and stress response in immature versus differentiated cardiomyocyte cell lines.

Nat Commun. 2022 Oct 10. 13(1): 5859

Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes.

Shin-Ichi Ikeda, Toshihide Kurihara, Xiaoyan Jiang, Yukihiro Miwa, Deokho Lee, Naho Serizawa, Heonuk Jeong, Kiwako Mori, Yusaku Katada, Hiromitsu Kunimi, Nobuhiro Ozawa, Chiho Shoda, Mari Ibuki, Kazuno Negishi, Hidemasa Torii, Kazuo Tsubota.

Axial length is the primary determinant of eye size, and it is elongated in myopia. However, the underlying mechanism of the onset and progression of axial elongation remain unclear. Here, we show that endoplasmic reticulum (ER) stress in sclera is an essential regulator of axial elongation in myopia development through activation of both PERK and ATF6 axis followed by scleral collagen remodeling. Mice with lens-induced myopia (LIM) showed ER stress in sclera. Pharmacological interventions for ER stress could induce or inhibit myopia progression. LIM activated all IRE1, PERK and ATF6 axis, and pharmacological inhibition of both PERK and ATF6 suppressed myopia progression, which was confirmed by knocking down above two genes via CRISPR/Cas9 system. LIM dramatically changed the expression of scleral collagen genes responsible for ER stress. Furthermore, collagen fiber thinning and expression of dysregulated collagens in LIM were ameliorated by 4-PBA administration. We demonstrate that scleral ER stress and PERK/ATF6 pathway controls axial elongation during the myopia development in vivo model and 4-PBA eye drop is promising drug for myopia suppression/treatment.

DOI: https://doi.org/10.1038/s41467-022-33605-1
Cancers (Basel). 2022 Oct 05. pii: 4870. [Epub ahead of print]14(19):

The Role of the Hypoxia-Related Unfolded Protein Response (UPR) in the Tumor Microenvironment.

Sylwia Bartoszewska, James F Collawn, Rafal Bartoszewski.

  Despite our understanding of the unfolded protein response (UPR) pathways, the crosstalk between the UPR and the complex signaling networks that different cancers utilize for cell survival remains to be, in most cases, a difficult research barrier. A major problem is the constant variability of different cancer types and the different stages of cancer as well as the complexity of the tumor microenvironments (TME). This complexity often leads to apparently contradictory results. Furthermore, the majority of the studies that have been conducted have utilized two-dimensional in vitro cultures of cancer cells that were exposed to continuous hypoxia, and this approach may not mimic the dynamic and cyclic conditions that are found in solid tumors. Here, we discuss the role of intermittent hypoxia, one of inducers of the UPR in the cellular component of TME, and the way in which intermittent hypoxia induces high levels of reactive oxygen species, the activation of the UPR, and the way in which cancer cells modulate the UPR to aid in their survival. Although the past decade has resulted in defining the complex, novel non-coding RNA-based regulatory networks that modulate the means by which hypoxia influences the UPR, we are now just to beginning to understand some of the connections between hypoxia, the UPR, and the TME.

Keywords:  ER-stress; TME; UPRmt; cell fate determination; hypoxia-reoxygenation injury

DOI:  https://doi.org/10.3390/cancers14194870
Proc Natl Acad Sci U S A. 2022 Oct 18. 119(42): e2202133119

Bip-Yorkie interaction determines oncogenic and tumor-suppressive roles of Ire1/Xbp1s activation.

Shuai Yang, Hua Jiang, Weixiang Bian, Wenyan Xu, Yifan Guo, Sha Song, Jiadong Zheng, Xiaoyu Kuang, Chenxi Wu, Xiang Ding, Xiaowei Guo, Lei Xue, Zijing Yu, Yongdeng Zhang, Hyung Don Ryoo, Xu Li, Xianjue Ma.

  Unfolded protein response (UPR) is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. ER proteostasis is essential to adapt to cell proliferation and regeneration in development and tumorigenesis, but mechanisms linking UPR, growth control, and cancer progression remain unclear. Here, we report that the Ire1/Xbp1s pathway has surprisingly oncogenic and tumor-suppressive roles in a context-dependent manner. Activation of Ire1/Xbp1s up-regulates their downstream target Bip, which sequesters Yorkie (Yki), a Hippo pathway transducer, in the cytoplasm to restrict Yki transcriptional output. This regulation provides an endogenous defensive mechanism in organ size control, intestinal homeostasis, and regeneration. Unexpectedly, Xbp1 ablation promotes tumor overgrowth but suppresses invasiveness in a Drosophila cancer model. Mechanistically, hyperactivated Ire1/Xbp1s signaling in turn induces JNK-dependent developmental and oncogenic cell migration and epithelial-mesenchymal transition (EMT) via repression of Yki. In humans, a negative correlation between XBP1 and YAP (Yki ortholog) target gene expression specifically exists in triple-negative breast cancers (TNBCs), and those with high XBP1 or HSPA5 (Bip ortholog) expression have better clinical outcomes. In human TNBC cell lines and xenograft models, ectopic XBP1s or HSPA5 expression alleviates tumor growth but aggravates cell migration and invasion. These findings uncover a conserved crosstalk between the Ire1/Xbp1s and Hippo signaling pathways under physiological settings, as well as a crucial role of Bip-Yki interaction in tumorigenesis that is shared from Drosophila to humans.

Keywords:  Hippo signaling; size control; triple-negative breast cancer; tumorigenesis; unfolded protein response

DOI:  https://doi.org/10.1073/pnas.2202133119
Exp Cell Res. 2022 Oct 06. pii: S0014-4827(22)00369-X. [Epub ahead of print]421(1): 113376

IRE1α-XBP1 regulates PDK1-dependent induction of epithelial-mesenchymal transition in non-small cell lung cancer cells.

Xike Mao, Chenxi Yu, Feng Yin, Wenjiao Xu, Yonghan Pan, Bowen Yang, Tao Huang, Siling Chen, Wenge Luo, Tianyu Su, Zhihao Wu.

  Mounting evidence indicates that activation of unfolded protein response (UPR) and metabolic reprogramming contribute to cancer cell migration and invasion, but the molecular mechanism of pro-EMT program through a coordinated action of UPR with metabolism has not been defined. In this study, we utilized ER stress-inducing reagent, thapsigargin (TG), to induced pharmacologic ER stress in lung cancer cells. Here. We report that the branch of UPR, IRE1α-XBP1 pathway plays a pivotal role in reprogramming lung cancer cell metabolism. At the molecular level, the expression of pyruvate dehydrogenase kinase-1 (PDK-1) is directly induced by XBP1 as a consequence of UPR activation, thus facilitating aerobic glycolysis and lactate production. We also demonstrated that PDK1 serves as a downstream element of UPR activation in induction of Snail and EMT program. In addition, PDK1-induced Snail was dependent on the lactate production derived from metabolic reprogramming. Our findings reveal a critical role of lactate in pro-invasion events and establishes a direct connection between ER-stress and metabolic reprogramming in facilitating cancer cell progression.

Keywords:  IRE1α-XBP1 pathway; Metabolic reprogramming; Pyruvate dehydrogenase kinase-1 (PDK-1); Snail; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/j.yexcr.2022.113376
Int J Mol Sci. 2022 Oct 05. pii: 11826. [Epub ahead of print]23(19):

Endoplasmic Reticulum Homeostasis Regulates TLR4 Expression and Signaling in Mast Cells.

Shatha Boukeileh, Odai Darawshi, Miriam Shmuel, Mohamed Mahameed, Thomas Wilhelm, Priya Dipta, Francesca Forno, Bellam Praveen, Michael Huber, Francesca Levi-Schaffer, Boaz Tirosh.

  The endoplasmic reticulum (ER) is a dynamic organelle that responds to demand in secretory proteins by undergoing expansion. The mechanisms that control the homeostasis of ER size and function involve the activation of the unfolded protein response (UPR). The UPR plays a role in various effector functions of immune cells. Mast cells (MCs) are highly granular tissue-resident cells and key drivers of allergic inflammation. Their diverse secretory functions in response to activation through the high-affinity receptor for IgE (FcεRI) suggest a role for the UPR in their function. Using human cord blood-derived MCs, we found that FcεRI triggering elevated the expression level and induced activation of the UPR transducers IRE1α and PERK, accompanied by expansion of the ER. In mouse bone marrow-derived MCs and peritoneal MCs, the ER underwent a more moderate expansion, and the UPR was not induced following MC activation. The deletion of IRE1α in mouse MCs did not affect proliferation, survival, degranulation, or cytokine stimulation following FcεRI triggering, but it did diminish the surface expression of TLR4 and the consequent response to LPS. A similar phenotype was observed in human MCs using an IRE1α inhibitor. Our data indicate that the ER of MCs, primarily of humans, undergoes a rapid remodeling in response to activation that promotes responses to TLR4. We suggest that IRE1α inhibition can be a strategy for inhibiting the hyperactivation of MCs by LPS over the course of allergic responses.

Keywords:  ER stress; ER-phagy; TLR4; UPR; asthma; mast cells

DOI:  https://doi.org/10.3390/ijms231911826
Front Cell Dev Biol. 2022 ;10 820949

A possible connection between reactive oxygen species and the unfolded protein response in lens development: From insight to foresight.

Lixiong Gao, Ni Jin, Zi Ye, Tianju Ma, Yang Huang, Hongyu Li, Jinlin Du, Zhaohui Li.

  The lens is a relatively special and simple organ. It has become an ideal model to study the common developmental characteristics among different organic systems. Lens development is a complex process influenced by numerous factors, including signals from the intracellular and extracellular environment. Reactive oxygen species (ROS) are a group of highly reactive and oxygen-containing molecules that can cause endoplasmic reticulum stress in lens cells. As an adaptive response to ER stress, lens cells initiate the unfolded protein response (UPR) to maintain normal protein synthesis by selectively increasing/decreasing protein synthesis and increasing the degradation of misfolded proteins. Generally, the UPR signaling pathways have been well characterized in the context of many pathological conditions. However, recent studies have also confirmed that all three UPR signaling pathways participate in a variety of developmental processes, including those of the lens. In this review, we first briefly summarize the three stages of lens development and present the basic profiles of ROS and the UPR. We then discuss the interconnections between lens development and these two mechanisms. Additionally, the potential adoption of human pluripotent stem-cell-based lentoids in lens development research is proposed to provide a novel perspective on future developmental studies.

Keywords:  PSCs; ROS; UPR; lens development; lentoid body

DOI:  https://doi.org/10.3389/fcell.2022.820949
Front Aging Neurosci. 2022 ;14 1014450

Editorial: Unfolded protein response (UPR): An impending target for multiple neurological disorders.

Arif Tasleem Jan, Safikur Rahman, Khurshid Ahmad, Rinki Minakshi.



Keywords:  aggregation; endoplasmic reticulum stress; neurological disorders; protein folding; proteinopathies; unfolded protein response

DOI:  https://doi.org/10.3389/fnagi.2022.1014450
Biochim Biophys Acta Mol Basis Dis. 2022 Oct 11. pii: S0925-4439(22)00241-1. [Epub ahead of print] 166570

Mitoregulin controls mitochondrial function and stress-adaptation response during early phase of endoplasmic reticulum stress in breast cancer cells.

Munkyung Choi, Keon Wook Kang.

  The proper regulation of mitochondrial function is important for cellular homeostasis. Especially, in cancer cells, dysregulation of mitochondria is associated with diverse cellular events such as metabolism, redox status, and stress responses. Mitoregulin (MTLN), a micro protein encoded by LINC00116, recently has been reported to control mitochondrial functions in skeletal muscle cells and adipocytes. However, the role of MTLN in cancer cells remains unclear. In the present study, we found that MTLN regulates membrane potential and reactive oxygen species (ROS) generation of mitochondria in breast cancer cells. Moreover, MTLN deficiency resulted in abnormal mitochondria-associated ER membranes (MAMs) formation, which is crucial for stress adaptation. Indeed, the MTLN-deficient breast cancer cells failed to successfully resolve ER (endoplasmic reticulum) stress, and cell vulnerability to ER-stress inducers was significantly enhanced by the downregulation of MTLN. In conclusion, MTLN controls stress-adaptation responses in breast cancer cells as a key regulator of mitochondria-ER harmonization, and thereby its expression level may serve as an indicator of the responsiveness of cancer cells to proteasome inhibitors.

Keywords:  ER stress; Mitochondria-associated ER membrane; Mitochondrial quality control; Mitoregulin

DOI:  https://doi.org/10.1016/j.bbadis.2022.166570
Brain Res. 2022 Oct 06. pii: S0006-8993(22)00340-7. [Epub ahead of print] 148116

Mitochondrial Unfolded Protein Response in Ischemia-Reperfusion Injury.

Ming-Xi Zhu, Xiao-Fei Ma, Xing Niu, Gui-Bo Fan, Yan Li.

  Mitochondrial unfolded protein response (UPRmt) is a mitochondrial stress response that activates the transcriptional program of mitochondrial chaperone proteins and proteases to keep protein homeostasis in mitochondria. Ischemia-reperfusion injury results in multiple severe clinical issues linked to high morbidity and mortality in various disorders. The pathophysiology and pathogenesis of ischemia-reperfusion injury are complex and multifactorial. Emerging evidence showed the roles of UPRmt signaling in ischemia-reperfusion injury. Herein, we discuss the regulatory mechanisms underlying UPRmt signaling in C. elegans and mammals. Furthermore, we review the recent studies into the roles and mechanisms of UPRmt signaling in ischemia-reperfusion injury of the heart, brain, kidney, and liver. Further research of UPRmt signaling will potentially develop novel therapeutic strategies against ischemia-reperfusion injury.

Keywords:  ischemia-reperfusion injury; mitochondrial dysfunction; mitochondrial homeostasis; mitochondrial unfolded protein response

DOI:  https://doi.org/10.1016/j.brainres.2022.148116
FEBS Open Bio. 2022 Oct 10.

Knockdown of TMEM160 leads to an increase in reactive oxygen species generation and the induction of the mitochondrial unfolded protein response.

Kosei Yamashita, Misa Haraguchi, Masato Yano.

  Transmembrane protein 160 (TMEM160) was recently reported to be localized to the mitochondrial inner membrane, but mitochondrial function was noted to be unaffected by loss of TMEM160. In contrast to these previously published findings, we report here that the absence of TMEM160 influences intracellular responses. After confirming that TMEM160 is localized in the inner mitochondrial membrane, we knocked down TMEM160 in human cultured cells and analyzed the changes in cellular responses. TMEM160 depletion led to an upregulation of the mitochondrial chaperone HSPD1, suggesting that depletion induced the mitochondrial unfolded protein response (UPRmt ). Indeed, the expression of key transcription factors that induce the UPRmt (ATF4, ATF5, and DDIT3) was increased following TMEM160 depletion. Expression of the mitochondrial protein import-receptors TOMM22 and TOMM20 was also enhanced. In addition, we observed a significant increase in reactive oxygen species (ROS) generation following TMEM160 depletion. Glutathione S-transferases, which detoxify the products of oxidative stress, were also upregulated in TMEM160-depleted cells. Immunoblot analysis was performed to detect proteins modified by 4-hydroxynonenal (which is released after the peroxidation of lipids by ROS): the expression patterns of 4-hydroxynonenal-modified proteins were altered after TMEM160 depletion, suggesting that depletion enhanced degadation of these proteins. HSPD1, TOMM22, ATF4, ATF5, and DDIT3 remained upregulated after ROS was scavenged by N-acetylcysteine, suggesting that once the UPRmt is induced by TMEM160 depletion, it is not suppresed by the subsequent detoxification of ROS. These findings suggest that TMEM160 may suppress ROS generation and stabilize mitochondrial protein(s).

Keywords:  TMEM160; mitochondria; mitochondrial unfolded protein response; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1002/2211-5463.13496
Biochem Biophys Res Commun. 2022 Sep 29. pii: S0006-291X(22)01360-2. [Epub ahead of print]632 158-164

KIRA8 attenuates non-alcoholic steatohepatitis through inhibition of the IRE1α/XBP1 signalling pathway.

Shiting Zhao, Xiaomin Liu, Lei Li, Xinyu Kong, Wei Sun, Kerry Loomes, Tao Nie, Xiaoyan Hui, Donghai Wu.

  Endoplasmic reticulum (ER) stress is enhanced in non-alcoholic steatohepatitis (NASH). Among three signalling pathways, the IRE1α/XBP1 signalling pathway is strongly implicated in the pathogenesis of NASH but its significance is still largely uncharacterised. In this report, we constructed a hepatocyte-specific XBP1-Luciferase knock-in mouse model that allows in vivo monitoring of the IRE1α/XBP1 activity in hepatocytes. Using this mouse model, we found that IRE1α/XBP1 was activated within hepatocytes during the pathogenesis of NASH. Significantly, a specific IRE1α kinase-inhibiting RNase attenuator, KIRA8, attenuated NASH in mice. In conclusion, our hepatocyte-specific XBP1 splicing reporter mouse represents a valid model for research and drug development of NASH, which showed that the IRE1α-induced XBP splicing is potentiated in hepatocytes during pathogenesis of NASH. Furthermore, we carried out the proof-of-concept study to demonstrate that the allosteric IRE1α RNase inhibitor serves as a promising therapeutic agent for the treatment of NASH.

Keywords:  IRE1α; KIRA8; NASH; Reporter mouse model; XBP1 splicing

DOI:  https://doi.org/10.1016/j.bbrc.2022.09.098
Front Cell Dev Biol. 2022 ;10 1011639

Inhibition of mitochondrial respiration has fundamentally different effects on proliferation, cell survival and stress response in immature versus differentiated cardiomyocyte cell lines.

Bent Grün, Michaela Tirre, Simon Pyschny, Vijay Singh, Hans-Gerd Kehl, Christian Jux, Jörg-Detlef Drenckhahn.

  Myocardial tissue homeostasis is critically important for heart development, growth and function throughout the life course. The loss of cardiomyocytes under pathological conditions ultimately leads to cardiovascular disease due to the limited regenerative capacity of the postnatal mammalian heart. Inhibition of electron transport along the mitochondrial respiratory chain causes cellular stress characterized by ATP depletion as well as excessive generation of reactive oxygen species. Adult cardiomyocytes are highly susceptible to mitochondrial dysfunction whereas embryonic cardiomyocytes in the mouse heart have been shown to be resistant towards mitochondrial complex III inhibition. To functionally characterize the molecular mechanisms mediating this stress tolerance, we used H9c2 cells as an in vitro model for immature cardiomyoblasts and treated them with various inhibitors of mitochondrial respiration. The complex I inhibitor rotenone rapidly induced cell cycle arrest and apoptosis whereas the complex III inhibitor antimycin A (AMA) had no effect on proliferation and only mildly increased cell death. HL-1 cells, a differentiated and contractile cardiomyocyte cell line from mouse atrium, were highly susceptible to AMA treatment evident by cell cycle arrest and death. AMA induced various stress response mechanisms in H9c2 cells, such as the mitochondrial unfolded protein response (UPRmt), integrated stress response (ISR), heat shock response (HSR) and antioxidative defense. Inhibition of the UPR, ISR and HSR by siRNA mediated knock down of key components does not impair growth of H9c2 cells upon AMA treatment. In contrast, knock down of NRF2, an important transcriptional regulator of genes involved in detoxification of reactive oxygen species, reduces growth of H9c2 cells upon AMA treatment. Various approaches to activate cell protective mechanisms and alleviate oxidative stress in HL-1 cells failed to rescue them from AMA induced growth arrest and death. In summary, these data show that the site of electron transport interruption along the mitochondrial respiratory chain determines cell fate in immature cardiomyoblasts. The study furthermore points to fundamental differences in stress tolerance and cell survival between immature and differentiated cardiomyocytes which may underlie the growth plasticity of embryonic cardiomyocytes during heart development but also highlight the obstacles of cardioprotective therapies in the adult heart.

Keywords:  cardiomyocyte differentiation; cardiomyocyte proliferation; cardiomyocyte survival; cellular stress response; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.3389/fcell.2022.1011639