bims-unfpre 2023-07-23 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023–07–23
twelve papers selected by
Susan Logue, University of Manitoba

Endoplasmic reticulum stress: a novel targeted approach to repair bone defects by regulating osteogenesis and angiogenesis.
ER stress increases expression of intracellular calcium channel RyR1 to modify Ca2+ homeostasis in pancreatic beta cells.
Inhibition of MiR-106b-5p mediated by exosomes mitigates acute kidney injury by modulating transmissible endoplasmic reticulum stress and M1 macrophage polarization.
Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model.
Unconventional Activation of IRE1 Enhances TH17 Responses and Promotes Neutrophilic Airway Inflammation.
Endoplasmic reticulum stress and mitochondrial dysfunction during aging: Role of sphingolipids.
Unravelling the role of NFE2L1 in stress responses and related diseases.
Integrative analysis of genes reveals endoplasmic reticulum stress-related immune responses involved in dilated cardiomyopathy with fibrosis.
2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer's resilience.
A signal peptide peptidase is required for ER-symbiosome proximal association and protein secretion.
Innate Immunity, Epithelial Plasticity, and Remodeling in Asthma.
Metformin combined with glucose starvation synergistically suppress triple-negative breast cancer by enhanced unfolded protein response.

J Transl Med. 2023 Jul 18. 21(1): 480

Endoplasmic reticulum stress: a novel targeted approach to repair bone defects by regulating osteogenesis and angiogenesis.

Tingyu Wu, Yaping Jiang, Weipeng Shi, Yingzhen Wang, Tao Li.

  Bone regeneration therapy is clinically important, and targeted regulation of endoplasmic reticulum (ER) stress is important in regenerative medicine. The processing of proteins in the ER controls cell fate. The accumulation of misfolded and unfolded proteins occurs in pathological states, triggering ER stress. ER stress restores homeostasis through three main mechanisms, including protein kinase-R-like ER kinase (PERK), inositol-requiring enzyme 1ɑ (IRE1ɑ) and activating transcription factor 6 (ATF6), collectively known as the unfolded protein response (UPR). However, the UPR has both adaptive and apoptotic effects. Modulation of ER stress has therapeutic potential for numerous diseases. Repair of bone defects involves both angiogenesis and bone regeneration. Here, we review the effects of ER stress on osteogenesis and angiogenesis, with emphasis on ER stress under high glucose (HG) and inflammatory conditions, and the use of ER stress inducers or inhibitors to regulate osteogenesis and angiogenesis. In addition, we highlight the ability for exosomes to regulate ER stress. Recent advances in the regulation of ER stress mediated osteogenesis and angiogenesis suggest novel therapeutic options for bone defects.

Keywords:  Angiogenesis; Bone defects; Endoplasmic reticulum stress; Exosome; High glucose; Inflammation; Osteogenesis; Unfolded protein response

DOI:  https://doi.org/10.1186/s12967-023-04328-8
J Biol Chem. 2023 Jul 17. pii: S0021-9258(23)02093-8. [Epub ahead of print] 105065

ER stress increases expression of intracellular calcium channel RyR1 to modify Ca2+ homeostasis in pancreatic beta cells.

Irina X Zhang, Andrea Hermann, Juan Leon, Sivakumar Jeyarajan, Anoop Arunagiri, Peter Arvan, Patrick Gilon, Leslie S Satin.

  Pancreatic beta cells maintain glucose homeostasis by secreting pulses of insulin in response to a rise in plasma glucose. Pulsatile insulin secretion occurs as a result of glucose-induced oscillations in beta-cell cytosolic Ca2+. The endoplasmic reticulum (ER) helps regulate beta-cell cytosolic Ca2+, and ER stress can lead to ER Ca2+ reduction, beta-cell dysfunction, and an increased risk of type 2 diabetes. However, the mechanistic effects of ER stress on individual calcium channels is not well understood. To determine the effects of tunicamycin-induced ER stress on ER inositol 1,4,5-triphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) and their involvement in subsequent Ca2+ dysregulation, we treated INS-1 832/13 cells and primary mouse islets with ER stress inducer tunicamycin (TM). We showed TM treatment increased RyR1 mRNA without affecting RyR2 mRNA, and decreased both IP3R1 and IP3R3 mRNA. Furthermore, we found stress reduced ER Ca2+ levels, triggered oscillations in cytosolic Ca2+ under subthreshold glucose conditions, and increased apoptosis, and that these changes were prevented by cotreatment with the RyR1 inhibitor dantrolene. In addition, we demonstrate silencing RyR1 suppressed TM-induced subthreshold cytosolic Ca2+ oscillations, but silencing RyR2 did not affect these oscillations. In contrast, inhibiting IP3Rs with xestospongin-C failed to suppress the TM-induced cytosolic Ca2+ oscillations and did not protect beta cells from TM-induced apoptosis, although xestospongin-C inclusion did prevent ER Ca2+ reduction. Taken together, these results show changes in RyR1 play a critical role in ER stress-induced Ca2+ dysfunction and beta-cell apoptosis.

Keywords:  beta cells; calcium channels; endoplasmic reticulum stress (ER stress); inositol 1,4,5-triphosphate (IP(3)) receptor (IP(3)Rs); ryanodine receptor (RyRs)

DOI:  https://doi.org/10.1016/j.jbc.2023.105065
J Cell Mol Med. 2023 Jul 20.

Inhibition of MiR-106b-5p mediated by exosomes mitigates acute kidney injury by modulating transmissible endoplasmic reticulum stress and M1 macrophage polarization.

Xiang Li, Yanan Zhong, Rui Yue, Juan Xie, Yiyuan Zhang, Yongtao Lin, Hailun Li, Yong Xu, Donghui Zheng.

  Acute kidney injury (AKI), mainly caused by Ischemia/reperfusion injury (IRI), is a common and severe life-threatening disease with high mortality. Accumulating evidence suggested a direct relationship between endoplasmic reticulum (ER) stress response and AKI progression. However, the role of the transmissible ER stress response, a new modulator of cell-to-cell communication, in influencing intercellular communication between renal tubular epithelial cells (TECs) and macrophages in the AKI microenvironment remains to be determined. To address this issue, we first demonstrate that TECs undergoing ER stress are able to transmit ER stress to macrophages via exosomes, promoting macrophage polarization towards the pro-inflammatory M1 phenotype in vitro and in vivo. Besides, the miR-106b-5p/ATL3 signalling axis plays a pivotal role in the transmission of ER stress in the intercellular crosstalk between TECs and macrophages. We observed an apparent increase in the expression of miR-106b-5p in ER-stressed TECs. Furthermore, we confirmed that ALT3 is a potential target protein of miR-106b-5p. Notably, the inhibition of miR-106b-5p expression in macrophages not only restores ATL3 protein level but also decreases transmissible ER stress and hinders M1 polarization, thus alleviating AKI progression. Additionally, our results suggest that the level of exosomal miR-106b-5p in urine is closely correlated with the severity of AKI patients. Taken together, our study sheds new light on the crucial role of transmissible ER stress in the treatment of AKI through the regulation of the miR-106b-5p/ATL3 axis, offering new ideas for treating AKI.

Keywords:  acute kidney injury; endoplasmic reticulum stress; exosomes; ischemia-reperfusion; macrophages

DOI:  https://doi.org/10.1111/jcmm.17848
Exp Mol Med. 2023 Jul 18.

Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model.

Jung-Eun Park, Jiyoun Lee, Soonhyuck Ok, Seunghee Byun, Eun-Ju Chang, Sung-Eun Yoon, Young-Joon Kim, Min-Ji Kang.

The endoplasmic reticulum (ER) is a subcellular organelle essential for cellular homeostasis. Perturbation of ER functions due to various conditions can induce apoptosis. Chronic ER stress has been implicated in a wide range of diseases, including autosomal dominant retinitis pigmentosa (ADRP), which is characterized by age-dependent retinal degeneration caused by mutant rhodopsin alleles. However, the signaling pathways that mediate apoptosis in response to ER stress remain poorly understood. In this study, we performed an unbiased in vivo RNAi screen with a Drosophila ADRP model and found that Wg/Wnt1 mediated apoptosis. Subsequent transcriptome analysis revealed that ER stress-associated serine protease (Erasp), which has been predicted to show serine-type endopeptidase activity, was a downstream target of Wg/Wnt1 during ER stress. Furthermore, knocking down Erasp via RNAi suppressed apoptosis induced by mutant rhodopsin-1 (Rh-1P37H) toxicity, alleviating retinal degeneration in the Drosophila ADRP model. In contrast, overexpression of Erasp resulted in enhanced caspase activity in Drosophila S2 cells treated with apoptotic inducers and the stabilization of the initiator caspase Dronc (Death regulator Nedd2-like caspase) by stimulating DIAP1 (Drosophila inhibitor of apoptosis protein 1) degradation. These findings helped identify a novel cell death signaling pathway involved in retinal degeneration in an autosomal dominant retinitis pigmentosa model.

DOI: https://doi.org/10.1038/s12276-023-01044-7
bioRxiv. 2023 Jul 08. pii: 2023.06.30.547286. [Epub ahead of print]

Unconventional Activation of IRE1 Enhances TH17 Responses and Promotes Neutrophilic Airway Inflammation.

Dandan Wu, Xing Zhang, Kourtney M Zimmerly, Ruoning Wang, Amanda Livingston, Takao Iwawaki, Ashok Kumar, Xiang Wu, Michael A Mandell, Meilian Liu, Xuexian O Yang.

Treatment-refractory severe asthma manifests a neutrophilic phenotype associated with TH17 responses. Heightened unfolded protein responses (UPRs) are associated with the risk of asthma, including severe asthma. However, how UPRs participate in the deregulation of TH17 cells leading to this type of asthma remains elusive. In this study, we investigated the role of the UPR sensor IRE1 in TH17 cell function and neutrophilic airway inflammation. We found that IRE1 is induced in fungal asthma and is highly expressed in TH17 cells relative to naïve CD4 + T cells. Cytokine (e.g. IL-23) signals induce the IRE1-XBP1s axis in a JAK2-dependent manner. This noncanonical activation of the IRE1-XBP1s pathway promotes UPRs and cytokine secretion by TH17 cells. Ern1 (encoding IRE1)-deficiency decreases the expression of ER stress factors and impairs the differentiation and cytokine secretion of TH17 cells. Genetic ablation of Ern1 leads to alleviated TH17 responses and airway neutrophilia in a Candida albicans asthma model. Consistently, IL-23 activates the JAK2-IRE1-XBP1s pathway in vivo and enhances TH17 responses and neutrophilic infiltration into the airway. Taken together, our data indicate that IRE1, noncanonically activated by cytokine signals, promotes neutrophilic airway inflammation through the UPR- mediated secretory function of TH17 cells. The findings provide a novel insight into the fundamental understanding of IRE1 in TH17-biased TH2-low asthma.

DOI: https://doi.org/10.1101/2023.06.30.547286
Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Jul 18. pii: S1388-1981(23)00090-2. [Epub ahead of print] 159366

Endoplasmic reticulum stress and mitochondrial dysfunction during aging: Role of sphingolipids.

Qun Chen, Anna Kovilakath, Jeremy Allegood, Jeremy Thompson, Ying Hu, L Ashley Cowart, Edward J Lesnefsky.

  The endoplasmic reticulum (ER) plays a key role in the regulation of protein folding, lipid synthesis, calcium homeostasis, and serves as a primary site of sphingolipid biosynthesis. ER stress (ER dysfunction) participates in the development of mitochondrial dysfunction during aging. Mitochondria are in close contact with the ER through shared mitochondria associated membranes (MAM). Alteration of sphingolipids contributes to mitochondria-driven cell injury. Cardiolipin is a phospholipid that is critical to maintain enzyme activity in the electron transport chain. The aim of the current study was to characterize the changes in sphingolipids and cardiolipin in ER, MAM, and mitochondria during the progression of aging in young (3 mo.), middle (18 mo.), and aged (24 mo.) C57Bl/6 mouse hearts. ER stress increased in hearts from 18 mo. mice and mice exhibited mitochondrial dysfunction by 24 mo. Hearts were pooled to isolate ER, MAM, and subsarcolemmal mitochondria (SSM). LC-MS/MS quantification of lipid content showed that aging increased ceramide content in ER and MAM. In addition, the contents of sphingomyelin and monohexosylceramides are also increased in the ER from aged mice. Aging increased the total cardiolipin content in the ER. Aging did not alter the total cardiolipin content in mitochondria or MAM yet altered the composition of cardiolipin with aging in line with increased oxidative stress compared to young mice. These results indicate that alteration of sphingolipids can contribute to the ER stress and mitochondrial dysfunction that occurs during aging.

Keywords:  Aging; Ceramide; Monohexosylceramides; Sphingomyelin; electron transport chain

DOI:  https://doi.org/10.1016/j.bbalip.2023.159366
Redox Biol. 2023 Jul 14. pii: S2213-2317(23)00220-3. [Epub ahead of print]65 102819

Unravelling the role of NFE2L1 in stress responses and related diseases.

Xingzhu Liu, Chang Xu, Wanglong Xiao, Nianlong Yan.

  The nuclear factor erythroid 2 (NF-E2)-related factor 1 (NFE2L1, also known as Nrf1) is a highly conserved transcription factor that belongs to the CNC-bZIP subfamily. Its significance lies in its control over redox balance, proteasome activity, and organ integrity. Stress responses encompass a series of compensatory adaptations utilized by cells and organisms to cope with extracellular or intracellular stress initiated by stressful stimuli. Recently, extensive evidence has demonstrated that NFE2L1 plays a crucial role in cellular stress adaptation by 1) responding to oxidative stress through the induction of antioxidative responses, and 2) addressing proteotoxic stress or endoplasmic reticulum (ER) stress by regulating the ubiquitin-proteasome system (UPS), unfolded protein response (UPR), and ER-associated degradation (ERAD). It is worth noting that NFE2L1 serves as a core factor in proteotoxic stress adaptation, which has been extensively studied in cancer and neurodegeneration associated with enhanced proteasomal stress. In these contexts, utilization of NFE2L1 inhibitors to attenuate proteasome "bounce-back" response holds tremendous potential for enhancing the efficacy of proteasome inhibitors. Additionally, abnormal stress adaptations of NFE2L1 and disturbances in redox and protein homeostasis contribute to the pathophysiological complications of cardiovascular diseases, inflammatory diseases, and autoimmune diseases. Therefore, a comprehensive exploration of the molecular basis of NFE2L1 and NFE2L1-mediated diseases related to stress responses would not only facilitate the identification of novel diagnostic and prognostic indicators but also enable the identification of specific therapeutic targets for NFE2L1-related diseases.

Keywords:  Adaptive responses; Cancer; NFE2L1; Neurodegeneration; Oxidative stress; Proteasome

DOI:  https://doi.org/10.1016/j.redox.2023.102819
Apoptosis. 2023 Jul 18.

Integrative analysis of genes reveals endoplasmic reticulum stress-related immune responses involved in dilated cardiomyopathy with fibrosis.

Wanpeng Li, Peiling Liu, Huilin Liu, Fuchun Zhang, Fu Yicheng, Yicheng Fu.

  Endoplasmic reticulum (ER) stress has been implicated in the mechanisms underlying the fibrotic process in dilated cardiomyopathy (DCM) and results in disease exacerbation; however, the molecular details of this mechanism remain unclear. Through microarray and bioinformatic analyses, we explored genetic alterations in myocardial fibrosis (MF) and identified potential biomarkers related to ER stress. We integrated two public microarray datasets, including 19 DCM and 16 control samples, and comprehensively analyzed differential expression, biological functions, molecular interactions, and immune infiltration levels. The immune cell signatures suggest that inflammatory immune imbalance may promote MF progression. Both innate and adaptive immunity are involved in MF development, and T-cell subsets account for a considerable proportion of immune infiltration. The immune subtypes were further compared, and 103 differentially expressed ER stress-related genes were identified. These genes were mainly enriched in neuronal apoptosis, protein modification, oxidative stress reaction, glycolysis and gluconeogenesis, and NOD-like receptor signaling pathways. Furthermore, the 15 highest-scoring core genes were identified. Seven hub genes (AK1, ARPC3, GSN, KPNA2, PARP1, PFKL, and PRKC) might participate in immune-related mechanisms. Our results offer a new integrative view of the pathways and interaction networks of ER stress-related genes and provide guidance for developing novel therapeutic strategies for MF.

Keywords:  Bioinformatics; Dilated cardiomyopathy; Endoplasmic reticulum stress; Immune cells; Myocardial fibrosis

DOI:  https://doi.org/10.1007/s10495-023-01871-z
Neuron. 2023 Jul 11. pii: S0896-6273(23)00472-5. [Epub ahead of print]

2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer's resilience.

Amit Kumar, Saravanan S Karuppagounder, Yingxin Chen, Carlo Corona, Riki Kawaguchi, Yuyan Cheng, Mustafa Balkaya, Botir T Sagdullaev, Zhexing Wen, Charles Stuart, Sunghee Cho, Guo-Li Ming, Jürgen Tuvikene, Tõnis Timmusk, Daniel H Geschwind, Rajiv R Ratan.

  Intermittent fasting (IF) is a diet with salutary effects on cognitive aging, Alzheimer's disease (AD), and stroke. IF restricts a number of nutrient components, including glucose. 2-deoxyglucose (2-DG), a glucose analog, can be used to mimic glucose restriction. 2-DG induced transcription of the pro-plasticity factor, Bdnf, in the brain without ketosis. Accordingly, 2-DG enhanced memory in an AD model (5xFAD) and functional recovery in an ischemic stroke model. 2-DG increased Bdnf transcription via reduced N-linked glycosylation, consequent ER stress, and activity of ATF4 at an enhancer of the Bdnf gene, as well as other regulatory regions of plasticity/regeneration (e.g., Creb5, Cdc42bpa, Ppp3cc, and Atf3) genes. These findings demonstrate an unrecognized role for N-linked glycosylation as an adaptive sensor to reduced glucose availability. They further demonstrate that ER stress induced by 2-DG can, in the absence of ketosis, lead to the transcription of genes involved in plasticity and cognitive resilience as well as proteostasis.

Keywords:  2-deoxyglucose; Alzheimer’s disease; N-linked glycosylation; activating transcription factor 4; brain-derived neurotrophic factor; cognitive function; endoplasmic reticulum stress; intermittent fasting; ischemic stroke; learning and memory

DOI:  https://doi.org/10.1016/j.neuron.2023.06.013
Nat Commun. 2023 07 19. 14(1): 4355

A signal peptide peptidase is required for ER-symbiosome proximal association and protein secretion.

Jian Yang, Niu Zhai, Yuhui Chen, Luying Wang, Rujin Chen, Huairong Pan.

During legume-rhizobia symbiosis, differentiation of the symbiosome (engulfed intracellular rhizobia) is necessary for successful nitrogen fixation. To control symbiosome differentiation, host cell subcellular components, e.g., ER (endoplasmic reticulum), must adapt robustly to ensure large-scale host protein secretion to the new organelle. However, the key components controlling the adaption of ER in nodule cells remain elusive. We report that Medicago BID1, a nodule-specific signal peptide peptidase (SPP), is central to ER structural dynamics and host protein secretion. In bid1, symbiosome differentiation is blocked. BID1 localizes specifically to the ER membrane and expresses exclusively in nodule cells with symbiosomes. In the wild type ER forms proximal association structures with symbiosomes, but not in bid1. Consequently, in bid1 excessive ER stress responses are induced and ER-to-symbiosome protein secretion is impaired. In summary, a nodule-specific SPP is necessary for ER-symbiosome proximal association, host protein secretion, and symbiosome differentiation.

DOI: https://doi.org/10.1038/s41467-023-40008-3
Adv Exp Med Biol. 2023 ;1426 265-285

Innate Immunity, Epithelial Plasticity, and Remodeling in Asthma.

Allan R Brasier.

  Innate immune responses (IIR) of the epithelium play a critical role in the initiation and progression of asthma. The core of the IIR is an intracellular signaling pathway activated by pattern recognition receptors (PRRs) to limit the spread of infectious organisms. This chapter will focus on the epithelium as the major innate sentinel cell and its role in acute exacerbations (AEs). Although the pathways of how the IIR activates the NFκB transcription factor, triggering cytokine secretion, dendritic cell activation, and Th2 polarization are well-described, recent exciting work has developed mechanistic insights into how chronic activation of the IIR is linked to mucosal adaptive responses. These adaptations include changes in cell state, now called epithelial-mesenchymal plasticity (EMP). EMP is a coordinated, genomic response to airway injury disrupting epithelial barrier function, expanding the basal lamina, and producing airway remodeling. EMP is driven by activation of the unfolded protein response (UPR), a transcriptional response producing metabolic shunting of glucose through the hexosamine biosynthetic pathway (HBP) to protein N-glycosylation. NFκB signaling and UPR activation pathways potentiate each other in remodeling the basement membrane. Understanding of injury-repair process of epithelium provides new therapeutic targets for precision approaches to the treatment of asthma exacerbations and their sequelae.

Keywords:  Acute exacerbations; Bromodomain containing protein 4 (BRD4); Chromatin remodeling; Club cells; Endoplasmic reticulum stress; Epithelial mesenchymal transition; Epithelial mesenchymal trophic unit (EMTU); Extracellular matrix (ECM); Inositol-requiring enzyme 1 (IRE1); Interferon; Mucosa; Plasticity; Secretoglobin; Sentinel cells; Unfolded protein response (UPR); X-box binding protein

DOI:  https://doi.org/10.1007/978-3-031-32259-4_13
Biochem Biophys Res Commun. 2023 Jul 14. pii: S0006-291X(23)00885-9. [Epub ahead of print]675 146-154

Metformin combined with glucose starvation synergistically suppress triple-negative breast cancer by enhanced unfolded protein response.

Ying Li, Qingqian Zhang, Jintao Yang, Weiping He, Yulan Jiang, Yu Chen, Yifan Wang.

  Metformin (MET) is a well-documented drug used in the treatment of type II diabetes. Recent studies have revealed its potential anti-tumor effects in various types of cancer. However, the dosage of MET required to exhibit anti-tumor activity is considerably higher than the clinically recommended dosage. In this study, we investigated the synergistical anti-tumor effect of glucose deprivation and MET in MDA-MB-231 cells, which represents a triple-negative breast cancer subtype (TNBC). Our findings demonstrate that glucose deprivation significantly enhances the anti-tumor activity of MET by reducing cell proliferation and increasing cell apoptosis. RNA-seq was performed to identify the key molecules involved in this process. Our results indicate that unfolded protein response of endoplasmic reticulum (UPRER) was significantly activated upon glucose starvation combining with MET compared to glucose starvation alone. Notably, the combined treatment significantly activated UPRER signaling pathway through ATF4/ATF3/CHOP axis, due to enhanced UPRER stress. In conclusion, our study suggests that the synergistic effects of MET and glucose deprivation suppress cell proliferation in TNBC by activating pro-apoptotic molecules through UPRER stress. These findings have potential implications for the anti-tumor application of MET in TNBC.

Keywords:  Endoplasmic reticulum stress; Glucose starvation; Metformin; Triple-negative breast cancer; Unfolded protein response

DOI:  https://doi.org/10.1016/j.bbrc.2023.07.029