bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022‒08‒28
eight papers selected by
Susan Logue
University of Manitoba
  1. Macrophages and neutrophils are necessary for ER stress-induced β cell loss.
  2. Restoring TRAILR2/DR5-Mediated Activation of Apoptosis upon Endoplasmic Reticulum Stress as a Therapeutic Strategy in Cancer.
  3. Role of endoplasmic reticulum stress in impaired neonatal lung growth and bronchopulmonary dysplasia.
  4. ER-stress-induced secretion of circulating glucose-regulated protein 78kDa (GRP78) ameliorates pulmonary artery smooth muscle cell remodelling.
  5. Endoplasmic Reticulum Stress-Related Signature for Predicting Prognosis and Immune Features in Hepatocellular Carcinoma.
  6. Endoplasmic reticulum stress: A common pharmacologic target of cardioprotective drugs.
  7. Involvement of Bid in the crosstalk between ferroptotic agent-induced ER stress and TRAIL-induced apoptosis.
  8. Blocking CHOP-dependent TXNIP shuttling to mitochondria attenuates albuminuria and mitigates kidney injury in nephrotic syndrome.
  1. Cell Rep. 2022 Aug 23. pii: S2211-1247(22)01073-7. [Epub ahead of print]40(8): 111255
    Macrophages and neutrophils are necessary for ER stress-induced β cell loss.
    Bingyuan Yang, Liu Yang, Yueyang Wang, Lisette A Maddison, Zihan Tang, Sander Haigh, Yulong Gong, Yue Zhang, Brittney A Covington, Karin J Bosma, Xin Tong, Patrick Page-McCaw, Maureen Gannon, Qing Deng, Wenbiao Chen.
      Persistent endoplasmic reticulum (ER) stress induces islet inflammation and β cell loss. How islet inflammation contributes to β cell loss remains uncertain. We have reported previously that chronic overnutrition-induced ER stress in β cells causes Ripk3-mediated islet inflammation, macrophage recruitment, and a reduction of β cell numbers in a zebrafish model. We show here that β cell loss results from the intricate communications among β cells, macrophages, and neutrophils. Macrophage-derived Tnfa induces cxcl8a in β cells. Cxcl8a, in turn, attracts neutrophils to macrophage-contacted "hotspots" where β cell loss occurs. We also show potentiation of chemokine expression in stressed mammalian β cells by macrophage-derived TNFA. In Akita and db/db mice, there is an increase in CXCL15-positive β cells and intra-islet neutrophils. Blocking neutrophil recruitment in Akita mice preserves β cell mass and slows diabetes progression. These results reveal an important role of neutrophils in persistent ER stress-induced β cell loss.
    Keywords:  CP; ER stress; Metabolism; diabetes; islet inflammation; macrophages; neutrophils; overnutrition; zebrafish; β cell loss
    DOI:  https://doi.org/10.1016/j.celrep.2022.111255
  2. Int J Mol Sci. 2022 Aug 12. pii: 8987. [Epub ahead of print]23(16):
    Restoring TRAILR2/DR5-Mediated Activation of Apoptosis upon Endoplasmic Reticulum Stress as a Therapeutic Strategy in Cancer.
    Rocío Mora-Molina, Abelardo López-Rivas.
      The uncontrolled proliferation of malignant cells in growing tumors results in the generation of different stressors in the tumor microenvironment, such as nutrient shortage, hypoxia and acidosis, among others, that disrupt endoplasmic reticulum (ER) homeostasis and may lead to ER stress. As a response to ER stress, both normal and tumor cells launch a set of signaling pathways known as the unfolded protein response (UPR) to restore ER proteostasis and maintain cell viability and function. However, under sustained ER stress, an apoptotic cell death process can be induced and this has been the subject of different review articles, although the role of the TRAIL-R2/DR5-activated extrinsic pathway of apoptosis has not yet been thoroughly summarized. In this Review, we provide an updated overview of the molecular mechanisms regulating cell fate decisions in tumor cells undergoing ER stress and discuss the role of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) in the final outcome of UPR signaling. Particularly, we focus on the mechanisms controlling cellular FLICE-like inhibitory protein (FLIP) levels in tumor cells undergoing ER stress, which may represent a potential target for therapeutic intervention in cancer.
    Keywords:  FLIP; TRAILR2/DR5; apoptosis; cancer; endoplasmic reticulum stress; extrinsic pathway; tumor microenvironment; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms23168987
  3. PLoS One. 2022 ;17(8): e0269564
    Role of endoplasmic reticulum stress in impaired neonatal lung growth and bronchopulmonary dysplasia.
    Kirkwood A Pritchard, Xigang Jing, Michelle Teng, Clive Wells, Shuang Jia, Adeleye J Afolayan, Jason Jarzembowski, Billy W Day, Stephen Naylor, Martin J Hessner, G Ganesh Konduri, Ru-Jeng Teng.
      Myeloperoxidase (MPO), oxidative stress (OS), and endoplasmic reticulum (ER) stress are increased in the lungs of rat pups raised in hyperoxia, an established model of bronchopulmonary dysplasia (BPD). However, the relationship between OS, MPO, and ER stress has not been examined in hyperoxia rat pups. We treated Sprague-Dawley rat pups with tunicamycin or hyperoxia to determine this relationship. ER stress was detected using immunofluorescence, transcriptomic, proteomic, and electron microscopic analyses. Immunofluorescence observed increased ER stress in the lungs of hyperoxic rat BPD and human BPD. Proteomic and morphometric studies showed that tunicamycin directly increased ER stress of rat lungs and decreased lung complexity with a BPD phenotype. Previously, we showed that hyperoxia initiates a cycle of destruction that we hypothesized starts from increasing OS through MPO accumulation and then increases ER stress to cause BPD. To inhibit ER stress, we used tauroursodeoxycholic acid (TUDCA), a molecular chaperone. To break the cycle of destruction and reduce OS and MPO, we used N-acetyl-lysyltyrosylcysteine amide (KYC). The fact that TUDCA improved lung complexity in tunicamycin- and hyperoxia-treated rat pups supports the idea that ER stress plays a causal role in BPD. Additional support comes from data showing TUDCA decreased lung myeloid cells and MPO levels in the lungs of tunicamycin- and hyperoxia-treated rat pups. These data link OS and MPO to ER stress in the mechanisms mediating BPD. KYC's inhibition of ER stress in the tunicamycin-treated rat pup's lung provides additional support for the idea that MPO-induced ER stress plays a causal role in the BPD phenotype. ER stress appears to expand our proposed cycle of destruction. Our results suggest ER stress evolves from OS and MPO to increase neonatal lung injury and impair growth and development. The encouraging effect of TUDCA indicates that this compound has the potential for treating BPD.
    DOI:  https://doi.org/10.1371/journal.pone.0269564
  4. Cell Stress Chaperones. 2022 Aug 27.
    ER-stress-induced secretion of circulating glucose-regulated protein 78kDa (GRP78) ameliorates pulmonary artery smooth muscle cell remodelling.
    Muntadher Al Zaidi, Carmen Pizarro, Carolin Bley, Elena Repges, Alexander Sedaghat, Sebastian Zimmer, Felix Jansen, Vedat Tiyerili, Georg Nickenig, Dirk Skowasch, Adem Aksoy.
      Pulmonary arterial hypertension (PAH) is driven by vascular remodelling due to inflammation and cellular stress, including endoplasmic reticulum stress (ER stress). The main ER-stress chaperone, glucose-regulated protein 78 kDa (GRP78), is known to have protective effects in inflammatory diseases through extracellular signalling. The aim of this study is to investigate its significance in PAH. Human pulmonary arterial smooth muscle cells (PASMC) were stimulated with compounds that induce ER stress, after which the secretion of GRP78 into the cell medium was analysed by western blot. We found that when ER stress was induced in PASMC, there was also a time-dependent secretion of GRP78. Next, naïve PASMC were treated with conditioned medium (CM) from the ER-stressed donor PASMC. Incubation with CM from ER-stressed PASMC reduced the viability, oxidative stress, and expression of inflammatory and ER-stress markers in target cells. These effects were abrogated when the donor cells were co-treated with Brefeldin A to inhibit active secretion of GRP78. Direct treatment of PASMC with recombinant GRP78 modulated the expression of key inflammatory markers. Additionally, we measured GRP78 plasma levels in 19 PAH patients (Nice Group I) and correlated the levels to risk stratification according to ESC guidelines. Here, elevated plasma levels of GRP78 were associated with a favourable risk stratification. In conclusion, GRP78 is secreted by PASMC under ER stress and exhibits protective effects from the hallmarks of PAH in vitro. Circulating GRP78 may serve as biomarker for risk adjudication of patients with PAH. Proposed mechanism of ER-stress-induced GRP78 secretion by PASMC. Extracellular GRP78 can be measured as a circulating biomarker and is correlated with favourable clinical characteristics. Conditioned medium from ER-stressed PASMC reduces extensive viability, ROS formation, inflammation, and ER stress in target cells. These effects can be abolished by blocking protein secretion in donor cells by using Brefeldin A.
    Keywords:  Chaperone; ER stress; Pulmonary arterial hypertension; Vascular remodelling
    DOI:  https://doi.org/10.1007/s12192-022-01292-y
  5. J Immunol Res. 2022 ;2022 1366508
    Endoplasmic Reticulum Stress-Related Signature for Predicting Prognosis and Immune Features in Hepatocellular Carcinoma.
    Genhao Zhang, Jianping Sun.
      Hepatocellular carcinoma (HCC) with cancer cells under endoplasmic reticulum (ER) stress has a poor prognosis. This study is aimed at discovering credible biomarkers for predicting the prognosis of HCC based on ER stress-related genes (ERSRGs). We constructed a novel four-ERSRG prognostic risk model, including PON1, AGR2, SSR2, and TMCC1, through a series of bioinformatic approaches, which can accurately predict survival outcomes in HCC patients. Higher risk scores were linked to later grade, recurrence, advanced TNM stage, later T stage, and HBV infection. In addition, 20 fresh frozen tumors and normal tissues from HCC patients were collected and used to validate the genes expressed in the signature by qRT-PCR and immunohistochemical (IHC) assays. Moreover, we found the ER stress-related signature could reflect the infiltration levels of different immune cells in the tumor microenvironment (TME) and forecast the efficacy of immune checkpoint inhibitor (ICI) treatment. Finally, we created a nomogram incorporating this ER stress-related signature. In conclusion, our constructed four-gene risk model associated with ER stress can accurately predict survival outcomes in HCC patients, and the model's risk score is associated with the poor clinical classification.
    DOI:  https://doi.org/10.1155/2022/1366508
  6. Eur J Pharmacol. 2022 Aug 20. pii: S0014-2999(22)00482-4. [Epub ahead of print] 175221
    Endoplasmic reticulum stress: A common pharmacologic target of cardioprotective drugs.
    Arshag D Mooradian, Michael J Haas.
      Despite the advances made in cardiovascular disease prevention, there is still substantial residual risk of adverse cardiovascular events. Contemporary evidence suggests that additional reduction in cardiovascular disease risk can be achieved through amelioration of cellular stresses, notably inflammatory stress and endoplasmic reticulum (ER) stress. Only two clinical trials with anti-inflammatory agents have supported the role of inflammatory stress in cardiovascular risk. However, there are no clinical trials with selective ER stress modifiers to test the hypothesis that reducing ER stress can reduce cardiovascular disease. Nevertheless, the ER stress hypothesis is supported by recent pharmacologic studies revealing that currently available cardioprotective drugs share a common property of reducing ER stress. These drug classes include angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor blockers, β-adrenergic receptor blockers, statins, and select antiglycemic agents namely, metformin, glucagon like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors. Although these drugs ameliorate common risk factors for cardiovascular disease, such as hypertension, hypercholesterolemia and hyperglycemia, their cardioprotective effects may be partially independent of their principal effects on cardiovascular risk factors. Clinical trials with selective ER stress modifiers are needed to test the hypothesis that reducing ER stress can reduce cardiovascular disease.
    Keywords:  Cardioprotection; Cellular stress; Endoplasmic reticulum
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175221
  7. J Cell Physiol. 2022 Aug 22.
    Involvement of Bid in the crosstalk between ferroptotic agent-induced ER stress and TRAIL-induced apoptosis.
    Jin Hong Kim, Abdo J Najy, Jian Li, Xu Luo, Hyeong-Reh C Kim, Mohammad Haroon Asif Choudry, Yong J Lee.
      Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces death receptor-mediated extrinsic apoptosis, specifically in cancer cells, and Bid (BH3-interacting domain death agonist) plays an important role in TRAIL-induced apoptosis. Ferroptosis is a newly defined form of regulated cell death known to be distinct from other forms of cell death. However, our previous studies have shown that ferroptosis shares common pathways with other types of programmed cell death such as apoptosis. In this study, we investigated the role of Bid in the crosstalk between the ferroptotic agent-induced endoplasmic reticulum (ER) stress response and TRAIL-induced apoptosis. When human colorectal carcinoma HCT116 cells were treated with the ferroptosis-inducing agents artesunate and erastin in combination with TRAIL, TRAIL-induced activation of caspase-8 was enhanced, and subsequently, the truncation of Bid was increased. Similar results were observed when ovarian adenocarcinoma OVCAR-3 cells were treated with the ferroptotic agents in combination with TRAIL. Results from studies with Bid mutants reveal that the truncation of Bid and the presence of intact BH3 domains are critical for synergistic apoptosis. Nonfunctional Bid mutants were not able to activate the mitochondria-dependent apoptosis pathway, which is required for the conversion of p19 to p17, the active form of caspase-3. These results indicate that Bid plays a critical role in the crosstalk between the ferroptotic agent-induced ER stress response and TRAIL-induced apoptosis.
    Keywords:  Bid; TRAIL cytotoxicity; apoptosis; endoplasmic reticulum stress; ferroptosis
    DOI:  https://doi.org/10.1002/jcp.30863
  8. Proc Natl Acad Sci U S A. 2022 Aug 30. 119(35): e2116505119
    Blocking CHOP-dependent TXNIP shuttling to mitochondria attenuates albuminuria and mitigates kidney injury in nephrotic syndrome.
    Sun-Ji Park, Yeawon Kim, Chuang Li, Junwoo Suh, Jothilingam Sivapackiam, Tassia M Goncalves, George Jarad, Guoyan Zhao, Fumihiko Urano, Vijay Sharma, Ying Maggie Chen.
      Albuminuria is a hallmark of glomerular disease of various etiologies. It is not only a symptom of glomerular disease but also a cause leading to glomerulosclerosis, interstitial fibrosis, and eventually, a decline in kidney function. The molecular mechanism underlying albuminuria-induced kidney injury remains poorly defined. In our genetic model of nephrotic syndrome (NS), we have identified CHOP (C/EBP homologous protein)-TXNIP (thioredoxin-interacting protein) as critical molecular linkers between albuminuria-induced ER dysfunction and mitochondria dyshomeostasis. TXNIP is a ubiquitously expressed redox protein that binds to and inhibits antioxidant enzyme, cytosolic thioredoxin 1 (Trx1), and mitochondrial Trx2. However, very little is known about the regulation and function of TXNIP in NS. By utilizing Chop-/- and Txnip-/- mice as well as 68Ga-Galuminox, our molecular imaging probe for detection of mitochondrial reactive oxygen species (ROS) in vivo, we demonstrate that CHOP up-regulation induced by albuminuria drives TXNIP shuttling from nucleus to mitochondria, where it is required for the induction of mitochondrial ROS. The increased ROS accumulation in mitochondria oxidizes Trx2, thus liberating TXNIP to associate with mitochondrial nod-like receptor protein 3 (NLRP3) to activate inflammasome, as well as releasing mitochondrial apoptosis signal-regulating kinase 1 (ASK1) to induce mitochondria-dependent apoptosis. Importantly, inhibition of TXNIP translocation and mitochondrial ROS overproduction by CHOP deletion suppresses NLRP3 inflammasome activation and p-ASK1-dependent mitochondria apoptosis in NS. Thus, targeting TXNIP represents a promising therapeutic strategy for the treatment of NS.
    Keywords:  CHOP; ER stress; TXNIP; Trx2; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2116505119
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