bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022–04–10
ten papers selected by
Susan Logue, University of Manitoba
  1. Z-α1-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state.
  2. The IRE1α Inhibitor KIRA6 Blocks Leukotriene Biosynthesis in Human Phagocytes.
  3. Organelle Stress and Crosstalk in Kidney Disease.
  4. Endoplasmic Reticulum Stress of Oral Squamous Cell Carcinoma Induces Immunosuppression of Neutrophils.
  5. Zika virus infection accelerates Alzheimer's disease phenotypes in brain organoids.
  6. Prostaglandin E2-Induced AKT Activation Regulates the Life Span of Short-Lived Plasma Cells by Attenuating IRE1α Hyperactivation.
  7. MOXD1 knockdown suppresses the proliferation and tumor growth of glioblastoma cells via ER stress-inducing apoptosis.
  8. Spirocyclic dimer SpiD7 activates the unfolded protein response to selectively inhibit growth and induce apoptosis of cancer cells.
  9. VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells.
  10. Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease.
  1. Sci Adv. 2022 Apr 08. 8(14): eabm2094
    Z-α1-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state.
    Joseph E Chambers, Nikita Zubkov, Markéta Kubánková, Jonathon Nixon-Abell, Ioanna Mela, Susana Abreu, Max Schwiening, Giulia Lavarda, Ismael López-Duarte, Jennifer A Dickens, Tomás Torres, Clemens F Kaminski, Liam J Holt, Edward Avezov, James A Huntington, Peter St George-Hyslop, Marina K Kuimova, Stefan J Marciniak.
      Misfolding of secretory proteins in the endoplasmic reticulum (ER) features in many human diseases. In α1-antitrypsin deficiency, the pathogenic Z variant aberrantly assembles into polymers in the hepatocyte ER, leading to cirrhosis. We show that α1-antitrypsin polymers undergo a liquid:solid phase transition, forming a protein matrix that retards mobility of ER proteins by size-dependent molecular filtration. The Z-α1-antitrypsin phase transition is promoted during ER stress by an ATF6-mediated unfolded protein response. Furthermore, the ER chaperone calreticulin promotes Z-α1-antitrypsin solidification and increases protein matrix stiffness. Single-particle tracking reveals that solidification initiates in cells with normal ER morphology, previously assumed to represent a healthy pool. We show that Z-α1-antitrypsin-induced hypersensitivity to ER stress can be explained by immobilization of ER chaperones within the polymer matrix. This previously unidentified mechanism of ER dysfunction provides a template for understanding a diverse group of related proteinopathies and identifies ER chaperones as potential therapeutic targets.
    DOI:  https://doi.org/10.1126/sciadv.abm2094
  2. Front Pharmacol. 2022 ;13 806240
    The IRE1α Inhibitor KIRA6 Blocks Leukotriene Biosynthesis in Human Phagocytes.
    Xiao Tang, Tarvi Teder, Bengt Samuelsson, Jesper Z Haeggström.
      The ER stress and Unfolded Protein Response (UPR) component inositol-requiring enzyme 1α (IRE1α) has been linked to inflammation and lipid mediator production. Here we report that the potent IRE1α inhibitor, KIRA6, blocks leukotriene biosynthesis in human phagocytes activated with lipopolysaccharide (LPS) plus N-formyl-methionyl-leucyl-phenylalanine (fMLP) or thapsigargin (Tg). The inhibition affects both leukotriene B4 (LTB4) and cysteinyl leukotriene (cys-LTs) production at submicromolar concentration. Macrophages made deficient of IRE1α were still sensitive to KIRA6 thus demonstrating that the compound's effect on leukotriene production is IRE1α-independent. KIRA6 did not exhibit any direct inhibitory effect on key enzymes in the leukotriene pathway, as assessed by phospholipase A2 (PLA2), 5-lipoxygenase (5-LOX), LTA4 hydrolase (LTA4H), and LTC4 synthase (LTC4S) enzyme activity measurements in cell lysates. However, we find that KIRA6 dose-dependently blocks phosphorylation of p38 and ERK, mitogen-activated protein kinases (MAPKs) that have established roles in activating cytosolic PLA2α (cPLA2α) and 5-LOX. The reduction of p38 and ERK phosphorylation is associated with a decrease in cPLA2α phosphorylation and attenuated leukotriene production. Furthermore, KIRA6 inhibits p38 activity, and molecular modelling indicates that it can directly interact with the ATP-binding pocket of p38. This potent and unexpected, non-canonical effect of KIRA6 on p38 and ERK MAPKs and leukotriene biosynthesis may account for some of the immune-modulating properties of this widely used IRE1α inhibitor.
    Keywords:  IRE1α; KIRA6; MAPKs; inflammation; leukotrienes
    DOI:  https://doi.org/10.3389/fphar.2022.806240
  3. Kidney360. 2020 Oct 29. 1(10): 1157-1164
    Organelle Stress and Crosstalk in Kidney Disease.
    Sho Hasegawa, Reiko Inagi.
      Organelles play important roles in maintaining cellular homeostasis. Organelle stress responses, especially in mitochondria, endoplasmic reticula (ER), and primary cilia, are deeply involved in kidney disease pathophysiology. Mitochondria are the center of energy production in most eukaryotic cells. Renal proximal tubular cells are highly energy demanding and abundant in mitochondria. Mitochondrial dysfunctions in association with energy metabolism alterations produce reactive oxygen species and promote inflammation in proximal tubular cells, resulting in progression of kidney disease. The ER play critical roles in controlling protein quality. Unfolded protein response (UPR) pathways are the adaptive response to ER stress for maintaining protein homeostasis. UPR pathway dysregulation under pathogenic ER stress often occurs in glomerular and tubulointerstitial cells and promotes progression of kidney disease. The primary cilia sense extracellular signals and maintain calcium homeostasis in cells. Dysfunction of the primary cilia in autosomal dominant polycystic kidney disease reduces the calcium concentration in proximal tubular cells, leading to increased cell proliferation and retention of cyst fluid. In recent years, the direct interaction at membrane contact sites has received increased attention in association with the development of imaging technologies. The part of the ER that is directly connected to mitochondria is termed the mitochondria-associated ER membrane (MAM), which regulates calcium homeostasis and phospholipid metabolism in cells. Disruption of MAM integrity collapses cellular homeostasis and leads to diseases such as diabetes and Alzheimer disease. This review summarizes recent research on organelle stress and crosstalk, and their involvement in kidney disease pathophysiology. In addition, potential treatment options that target organelle stress responses are discussed.
    Keywords:  AKI-to-CKD transition; ER stress; acute kidney injury; chronic kidney disease; lipid metabolism; mitochondria; organelle crosstalk; organelle stress; tubular inflammation; unfolded protein response (UPR)
    DOI:  https://doi.org/10.34067/KID.0002442020
  4. Front Oncol. 2022 ;12 818192
    Endoplasmic Reticulum Stress of Oral Squamous Cell Carcinoma Induces Immunosuppression of Neutrophils.
    Ching-Fang Wu, Tzu-Ting Hung, Yu-Chieh Su, Po-Jen Chen, Kuei-Hung Lai, Chih-Chun Wang.
      The endoplasmic reticulum (ER) stress of cancer cells not only determined cancer cell fate but also indirectly triggered proinflammatory or immunosuppressive responses of macrophages. In addition, ER stressed neutrophils were known to acquire immunosuppressive activity with surface expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). Since the importance of tumor ER stress and immunosuppressive neutrophils has been emphasized in head and neck cancers, we hypothesized that the ER stress of oral squamous cell carcinoma (OSCC) could transform neutrophils into LOX-1 expressing immunosuppressive phenotype. Two human OSCC cell lines, SCC25 and OML1, were treated with either vehicle or thapsigargin (THG), an ER stress inducer. These tumor conditioned media (TCM) were collected accordingly. Then human peripheral blood neutrophils from healthy donors were cultured in these TCM. The results showed that neutrophils cultured in THG-treated TCM had higher expression of LOX-1 compared with those cultured in vehicle-treated TCM. Moreover, by interleukin-2/anti-CD3/anti-CD28 activated autologous T cell proliferation assay, neutrophils conditioned by THG-treated TCM were shown to inhibit T cell proliferation more significantly than those conditioned by vehicle-treated TCM. These novel findings indicated that the ER stress of OSCC could be transmitted to neutrophils which in turn expressed LOX-1 and obtained immunosuppressive ability. Our findings further supported the existence of "transmissible" ER stress between tumor cells and neutrophils.
    Keywords:  endoplasmic reticulum stress; immunosuppression ; lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1); neutrophils; oral squamous cell carcinoma
    DOI:  https://doi.org/10.3389/fonc.2022.818192
  5. Cell Death Discov. 2022 Apr 02. 8(1): 153
    Zika virus infection accelerates Alzheimer's disease phenotypes in brain organoids.
    Seung-Eun Lee, Hanul Choi, Nari Shin, Dasom Kong, Nam Gyo Kim, Hee-Yeong Kim, Min-Ji Kim, Soon Won Choi, Young Bong Kim, Kyung-Sun Kang.
      Alzheimer's disease (AD) is one of the progressive neurodegenerative diseases characterized by β-amyloid (Aβ) production and Phosphorylated-Tau (p-Tau) protein in the cerebral cortex. The precise mechanisms of the cause, responsible for disease pathology and progression, are not well understood because there are multiple risk factors associated with the disease. Viral infection is one of the risk factors for AD, and we demonstrated that Zika virus (ZIKV) infection in brain organoids could trigger AD pathological features, including Aβ and p-Tau expression. AD-related phenotypes in brain organoids were upregulated via endoplasmic reticulum (ER) stress and unfolded protein response (UPR) after ZIKV infection in brain organoids. Under persistent ER stress, activated-double stranded RNA-dependent protein kinase-like ER-resident (PERK) triggered the phosphorylation of Eukaryotic initiation factor 2 (eIF2α) and then BACE, and GSK3α/β related to AD. Furthermore, we demonstrated that pharmacological inhibitors of PERK attenuated Aβ and p-Tau in brain organoids after ZIKV infection.
    DOI:  https://doi.org/10.1038/s41420-022-00958-x
  6. J Immunol. 2022 Apr 04. pii: ji2100466. [Epub ahead of print]
    Prostaglandin E2-Induced AKT Activation Regulates the Life Span of Short-Lived Plasma Cells by Attenuating IRE1α Hyperactivation.
    Wei Wang, Xiaodan Qin, Liang Lin, Jia Wu, Xiuyuan Sun, Ye Zhao, Yurong Ju, Ziheng Zhao, Liwei Ren, Xuewen Pang, Youfei Guan, Yu Zhang.
      The mechanism regulating the life span of short-lived plasma cells (SLPCs) remains poorly understood. Here we demonstrated that the EP4-mediated activation of AKT by PGE2 was required for the proper control of inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) hyperactivation and hence the endoplasmic reticulum (ER) homeostasis in IgM-producing SLPCs. Disruption of the PGE2-EP4-AKT signaling pathway resulted in IRE1α-induced activation of JNK, leading to accelerated death of SLPCs. Consequently, Ptger4-deficient mice (C57BL/6) exhibited a markedly impaired IgM response to T-independent Ags and increased susceptibility to Streptococcus pneumoniae infection. This study reveals a highly selective impact of the PGE2-EP4 signal on the humoral immunity and provides a link between ER stress response and the life span of SLPCs.
    DOI:  https://doi.org/10.4049/jimmunol.2100466
  7. Cell Death Discov. 2022 Apr 07. 8(1): 174
    MOXD1 knockdown suppresses the proliferation and tumor growth of glioblastoma cells via ER stress-inducing apoptosis.
    Pengfei Shi, Jie Xu, Fanwei Xia, Yinggang Wang, Jie Ren, Ping Liang, Hongjuan Cui.
      Oxygenase-catalyzed reduction and activation of oxygen molecules and the incorporation of oxygen atoms into organic molecules are undoubtedly necessary in the process of tumor development, and it is also one of the research hotspots in recent years. MOXD1 belongs to the copper-dependent monooxygenase family. The expression of MOXD1 is one of the characteristics of early tumor development. However, it is not understandable that the biological function and molecular mechanism of MOXD1 in Glioblastoma (GBM). In this study, high MOXD1 expression is strongly associated with poor survival of the patient with GBM. Moreover. MOXD1 knockdown can inhibit cell viability, proliferation, migration, invasion, and tumorigenesis of GBM cells. This is also proven for the first time that MOXD1 can bind to β3GnT2 and affect the glycosylation modification of some proteins. In addition, knockdown of MOXD1 induces endoplasmic reticulum (ER) stress and triggers the ER-mitochondrial apoptosis pathway. Taken together, these results reveal that MOXD1 is involved in the occurrence and development of GBM, and also provide a new strategy for targeted therapy.
    DOI:  https://doi.org/10.1038/s41420-022-00976-9
  8. J Biol Chem. 2022 Apr 01. pii: S0021-9258(22)00330-1. [Epub ahead of print] 101890
    Spirocyclic dimer SpiD7 activates the unfolded protein response to selectively inhibit growth and induce apoptosis of cancer cells.
    Smit Kour, Sandeep Rana, Sydney P Kubica, Smitha Kizhake, Mudassier Ahmad, Catalina Muñoz-Trujillo, David Klinkebiel, Sarbjit Singh, Jayapal Reddy Mallareddy, Surabhi Chandra, Nicholas T Woods, Adam R Karpf, Amarnath Natarajan.
      The unfolded protein response (UPR) is an adaptation mechanism activated to resolve transient accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER). Failure to resolve the transient accumulation of such proteins results in UPR-mediated programmed cell death. Loss of tumor suppressor gene or oncogene addiction in cancer cells can result in sustained higher basal UPR levels; however, it is not clear if these higher basal UPR levels in cancer cells can be exploited as a therapeutic strategy. We hypothesized that covalent modification of surface-exposed cysteine (SEC) residues could simulate unfolded/misfolded proteins to activate the UPR, and that higher basal UPR levels in cancer cells would provide the necessary therapeutic window. To test this hypothesis, here we synthesized analogs that can covalently modify multiple SEC residues and evaluated them as UPR activators. We identified a spirocyclic dimer, SpiD7, and evaluated its effects on UPR activation signals, i.e., XBP1 splicing, phosphorylation of eIF2α, and a decrease in ATF6 levels, in normal and cancer cells, which were further confirmed by RNA-seq analyses. We found that SpiD7 selectively induced caspase-mediated apoptosis in cancer cells, while normal cells exhibited robust XBP1 splicing, indicating adaptation to ER stress. Furthermore, SpiD7 inhibited the growth of high-grade serous-carcinoma (HGSC) cell lines ∼3-15-fold more potently than immortalized fallopian tube epithelial (paired normal control) cells, and reduced clonogenic growth of HGSC cell lines. Our results suggest that induction of the UPR by covalent modification of SEC residues represents a cancer cell vulnerability and can be exploited to discover novel therapeutics.
    Keywords:  Small molecule; UPR; UPR activation; apoptosis; cancer cell vulnerability; isatin-derived spirocyclic dimer; protein misfolding
    DOI:  https://doi.org/10.1016/j.jbc.2022.101890
  9. PLoS One. 2022 ;17(4): e0266478
    VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells.
    Paweł P Szczęśniak, Jan B Heidelberger, Hubert Serve, Petra Beli, Sebastian A Wagner.
      Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the accumulation of undifferentiated white blood cells (blasts) in the bone marrow. Valosin-containing protein (VCP) is an abundant molecular chaperone that extracts ubiquitylated substrates from protein complexes and cellular compartments prior to their degradation by the proteasome. We found that treatment of AML cell lines with the VCP inhibitor CB-5083 leads to an accumulation of ubiquitylated proteins, activation of unfolded protein response (UPR) and apoptosis. Using quantitative mass spectrometry-based proteomics we assessed the effects of VCP inhibition on the cellular ubiquitin-modified proteome. We could further show that CB-5083 decreases the survival of the AML cell lines THP-1 and MV4-11 in a concentration-dependent manner, and acts synergistically with the antimetabolite cytarabine and the BH3-mimetic venetoclax. Finally, we showed that prolonged treatment of AML cells with CB-5083 leads to development of resistance mediated by mutations in VCP. Taken together, inhibition of VCP leads to a lethal unfolded protein response in AML cells and might be a relevant therapeutic strategy for treatment of AML, particularly when combined with other drugs. The toxicity and development of resistance possibly limit the utility of VCP inhibitors and have to be further explored in animal models and clinical trials.
    DOI:  https://doi.org/10.1371/journal.pone.0266478
  10. Cell Stem Cell. 2022 Apr 07. pii: S1934-5909(22)00101-1. [Epub ahead of print]
    Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease.
    Xinxiu Xu, Kang Jin, Abha S Bais, Wenjuan Zhu, Hisato Yagi, Timothy N Feinstein, Phong K Nguyen, Joseph D Criscione, Xiaoqin Liu, Gisela Beutner, Kalyani B Karunakaran, Krithika S Rao, Haoting He, Phillip Adams, Catherine K Kuo, Dennis Kostka, Gloria S Pryhuber, Sruti Shiva, Madhavi K Ganapathiraju, George A Porter, Jiuann-Huey Ivy Lin, Bruce Aronow, Cecilia W Lo.
      Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with 30% mortality from heart failure (HF) in the first year of life, but the cause of early HF remains unknown. Induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CM) from patients with HLHS showed that early HF is associated with increased apoptosis, mitochondrial respiration defects, and redox stress from abnormal mitochondrial permeability transition pore (mPTP) opening and failed antioxidant response. In contrast, iPSC-CM from patients without early HF showed normal respiration with elevated antioxidant response. Single-cell transcriptomics confirmed that early HF is associated with mitochondrial dysfunction accompanied with endoplasmic reticulum (ER) stress. These findings indicate that uncompensated oxidative stress underlies early HF in HLHS. Importantly, mitochondrial respiration defects, oxidative stress, and apoptosis were rescued by treatment with sildenafil to inhibit mPTP opening or TUDCA to suppress ER stress. Together these findings point to the potential use of patient iPSC-CM for modeling clinical heart failure and the development of therapeutics.
    Keywords:  TUDCA; antioxidant response; congenital heart disease; endoplasmic reticulum stress; heart failure; hypoplastic left heart syndrome; i; induced pluripotent stem-cell-derived cardiomyocytes; mitochondrial permeability transition pore; oxidative stress; sildenafil
    DOI:  https://doi.org/10.1016/j.stem.2022.03.003
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