bims-unfpre 2021-07-11 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2021–07–11
eleven papers selected by
Susan Logue, University of Manitoba

The Regulation of Animal Behavior by Cellular Stress Responses.
Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte β- selection.
Distinct mechanisms govern populations of myeloid-derived suppressor cells in chronic viral infection and cancer.
Hormetic endoplasmic reticulum stress in hematopoietic stem cells.
Small heterodimer partner (SHP) aggravates ER stress in Parkinson's disease-linked LRRK2 mutant astrocyte by regulating XBP1 SUMOylation.
IRE1-mTOR-PERK Axis Coordinates Autophagy and ER Stress-Apoptosis Induced by P2X7-Mediated Ca2+ Influx in Osteoarthritis.
Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression.
Regulation of redox signaling in HIF1-dependent tumor angiogenesis.
ATF6 promotes liver fibrogenesis by regulating macrophage-derived interleukin-1α expression.
Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide.
OASIS/CREB3L1 is a factor that responds to nuclear envelope stress.

Exp Cell Res. 2021 Jul 01. pii: S0014-4827(21)00252-4. [Epub ahead of print] 112720

The Regulation of Animal Behavior by Cellular Stress Responses.

Neşem P O Zbey, Maximilian A Thompson, Rebecca C Taylor.

  Cellular stress responses exist to detect the effects of stress on cells and to enact responses that protect from that stress. As well as acting at the cellular level, stress response pathways can also regulate whole organism responses to stress. One way in which animals facilitate their survival in stressful environments is through behavioral adaptation; this review considers the evidence that activation of cellular stress responses plays an important role in mediating the changes to behavior that promote organismal survival upon stress.

Keywords:  Stress response; UPR; behavior; signaling; transcription factor

DOI:  https://doi.org/10.1016/j.yexcr.2021.112720
Elife. 2021 Jul 09. pii: e69975. [Epub ahead of print]10

Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte β- selection.

Xia Liu, Jingjing Yu, Longyong Xu, Katharine Umphred-Wilson, Fanglue Peng, Yao Ding, Brendan M Barton, Xiangdong Lv, Michael Y Zhao, Shengyi Sun, Yuning Hong, Ling Qi, Stanley Adoro, Xi Chen.

  Signals from the pre-T cell receptor and Notch coordinately instruct b-selection of CD4-CD8- double negative (DN) thymocytes to generate ab T cells in the thymus. However, how these signals ensure a high-fidelity proteome and safeguard the clonal diversification of the pre-selection TCR repertoire given the considerable translational activity imposed by b-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint during b-selection. Expression of the SEL1L-HRD1 complex, the most conserved branch of ERAD, is directly regulated by the transcriptional activity of the Notch intracellular domain. Deletion of Sel1l impaired DN3 to DN4 thymocyte transition and severely impaired mouse ab T cell development. Mechanistically, Sel1l deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. Accordingly, genetically inactivating PERK rescued T cell development from Sel1l-deficient thymocytes. In contrast, IRE1a/XBP1 pathway was induced as a compensatory adaptation to alleviate Sel1l-deficiency induced ER stress. Dual loss of Sel1l and Xbp1 markedly exacerbated the thymic defect. Our study reveals a critical developmental signal controlled proteostasis mechanism that enforces T cell development to ensure a healthy adaptive immunity.

Keywords:  developmental biology; immunology; inflammation; mouse

DOI:  https://doi.org/10.7554/eLife.69975
J Clin Invest. 2021 Jul 06. pii: 145971. [Epub ahead of print]

Distinct mechanisms govern populations of myeloid-derived suppressor cells in chronic viral infection and cancer.

Evgenii N Tcyganov, Shino Hanabuchi, Ayumi Hashimoto, David Campbell, Gozde Kar, Timothy Wf Slidel, Corinne Cayatte, Aimee Landry, Fernanda Pilataxi, Susana Hayes, Brian Dougherty, Kristin C Hicks, Kathy Mulgrew, Chih-Hang A Tang, Chih-Chi A Hu, Wei Guo, Sergei Grivennikov, Mohammed-Alkhatim A Ali, Jean-Christophe Beltra, E John Wherry, Yulia Nefedova, Dmitry I Gabrilovich.

  Myeloid-derived suppressor cells (MDSC) are major negative regulators of immune responses in cancer and chronic infections. It remains unclear if regulation of MDSC activity at different conditions is controlled by similar mechanisms. We compared MDSC in mice with cancer and lymphocytic choriomeningitis virus (LCMV) infection. Chronic LCMV infection caused the development of monocytic - M-MDSC but did not induce polymorphonuclear - PMN-MDSC. In contrast, both MDSC populations were present in cancer models. An acquisition of immune suppressive activity by PMN-MDSC in cancer was controlled by IRE1α and ATF6 pathways of the endoplasmic reticulum (ER) stress response. Abrogation of PMN-MDSC activity by blockade of the ER stress response resulted in increase in tumor-specific immune response and reduced tumor progression. In contrast, the ER stress response was dispensable for suppressive activity of M-MDSC in cancer and LCMV infection. Acquisition of immune suppressive activity by M-MDSC in spleens was mediated by IFN-γ signaling. However, it was dispensable for suppressive activity of M-MDSC in tumor tissues. Suppressive activity of M-MDSC in tumors was retained due to the effect of IL-6 present at high concentrations in tumor site. These results demonstrate disease and population-specific mechanisms of MDSC accumulation and need for targeting of different pathways to achieve inactivation of these cells.

Keywords:  Immunology; Innate immunity; Monocytes; Neutrophils; Oncology

DOI:  https://doi.org/10.1172/JCI145971
Curr Opin Hematol. 2021 Jul 06.

Hormetic endoplasmic reticulum stress in hematopoietic stem cells.

Larry L Luchsinger.

PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) possess the ability to regenerate over a lifetime in the face of extreme cellular proliferation and environmental stress. Yet, mechanisms that control the regenerative properties of HSCs remain elusive. ER stress has emerged as an important signaling event that supports HSC self-renewal and multipotency. The purpose of this review is to summarize the pathways implicating ER stress as cytoprotective in HSCs.
RECENT FINDINGS: Recent studies have shown multiple signaling cascades of the unfolded protein response (UPR) are persistently activated in healthy HSCs, suggesting that low-dose ER stress is a feature HSCs. Stress adaptation is a feature ascribed to cytoprotection and longevity of cells as well as organisms, in what is known as hormesis. However, assembling this information into useful knowledge to improve the therapeutic application of HSCs remains challenging and the upstream activators and downstream transcriptional programs induced by ER stress that are required in HSCs remain to be discovered.
SUMMARY: The maintenance of HSCs requires a dose-dependent simulation of ER stress responses that involves persistent, low-dose UPR. Unraveling the complexity of this signaling node may elucidate mechanisms related to regeneration of HSCs that can be harnessed to expand HSCs for cellular therapeutics ex vivo and transplantation in vivo.

DOI: https://doi.org/10.1097/MOH.0000000000000668
J Biomed Sci. 2021 Jul 07. 28(1): 51

Small heterodimer partner (SHP) aggravates ER stress in Parkinson's disease-linked LRRK2 mutant astrocyte by regulating XBP1 SUMOylation.

Jee Hoon Lee, Ji-Hye Han, Eun-Hye Joe, Ilo Jou.

   BACKGROUND: Endoplasmic reticulum (ER) stress is a common feature of Parkinson's disease (PD), and several PD-related genes are responsible for ER dysfunction. Recent studies suggested LRRK2-G2019S, a pathogenic mutation in the PD-associated gene LRRK2, cause ER dysfunction, and could thereby contribute to the development of PD. It remains unclear, however, how mutant LRRK2 influence ER stress to control cellular outcome. In this study, we identified the mechanism by which LRRK2-G2019S accelerates ER stress and cell death in astrocytes.
METHODS: To investigate changes in ER stress response genes, we treated LRRK2-wild type and LRRK2-G2019S astrocytes with tunicamycin, an ER stress-inducing agent, and performed gene expression profiling with microarrays. The XBP1 SUMOylation and PIAS1 ubiquitination were performed using immunoprecipitation assay. The effect of astrocyte to neuronal survival were assessed by astrocytes-neuron coculture and slice culture systems. To provide in vivo proof-of-concept of our approach, we measured ER stress response in mouse brain.
RESULTS: Microarray gene expression profiling revealed that LRRK2-G2019S decreased signaling through XBP1, a key transcription factor of the ER stress response, while increasing the apoptotic ER stress response typified by PERK signaling. In LRRK2-G2019S astrocytes, the transcriptional activity of XBP1 was decreased by PIAS1-mediated SUMOylation. Intriguingly, LRRK2-GS stabilized PIAS1 by increasing the level of small heterodimer partner (SHP), a negative regulator of PIAS1 degradation, thereby promoting XBP1 SUMOylation. When SHP was depleted, XBP1 SUMOylation and cell death were reduced. In addition, we identified agents that can disrupt SHP-mediated XBP1 SUMOylation and may therefore have therapeutic activity in PD caused by the LRRK2-G2019S mutation.
CONCLUSION: Our findings reveal a novel regulatory mechanism involving XBP1 in LRRK2-G2019S mutant astrocytes, and highlight the importance of the SHP/PIAS1/XBP1 axis in PD models. These findings provide important insight into the basis of the correlation between mutant LRRK2 and pathophysiological ER stress in PD, and suggest a plausible model that explains this connection.

Keywords:  Astrocytes; ER stress; LRRK2; PIAS1; Parkinson’s diseases; SHP; SUMOylation; XBP1

DOI:  https://doi.org/10.1186/s12929-021-00747-1
Front Cell Dev Biol. 2021 ;9 695041

IRE1-mTOR-PERK Axis Coordinates Autophagy and ER Stress-Apoptosis Induced by P2X7-Mediated Ca2+ Influx in Osteoarthritis.

Zihao Li, Ziyu Huang, He Zhang, Jinghan Lu, Yingliang Wei, Yue Yang, Lunhao Bai.

  Moderate-intensity exercise can help delay the development of osteoarthritis (OA). Previous studies have shown that the purinergic receptor P2X ligand gated ion channel 7 (P2X7) is involved in OA development and progression. To investigate the effect of exercise on P2X7 activation and downstream signaling in OA, we used the anterior cruciate ligament transection (ACLT)-induced OA rat model and primary chondrocyte culture system. Our in vivo experiments confirmed that treadmill exercise increased P2X7 expression and that this effect was more pronounced at the later time points. Furthermore, P2X7 activation induced endoplasmic reticulum (ER) stress and increased the expression levels of ER stress markers, such as 78 kDa glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme-1 (IRE1), and activating transcription factor 6 (ATF6). At the early time points, IRE1 and PERK were activated, and mTOR was inhibited. At the later time points, mTOR was activated, mediating PERK to promote ER stress-apoptosis, whereas IRE1 and autophagy were inhibited. To confirm our observations in vitro, we treated primary chondrocytes with the P2X7 agonist benzoylbenzoyl-ATP (Bz-ATP). Our results confirmed that P2X7-mediated Ca2+ influx activated IRE1-mediated autophagic flux and induced PERK-mediated ER stress-apoptosis. To further investigate the role of P2X7 in OA, we injected mTOR antagonist rapamycin or P2X7 antagonist A740003 into the knee joints of ACLT rats. Our results demonstrated that mTOR inhibition induced autophagy, decreased apoptosis, and reduced cartilage loss. However, injection of mTOR agonist MHY1485 or Bz-ATP had the opposite effect. In summary, our results indicated that during the early stages of moderate-intensity exercise, P2X7 was activated and autophagic flux was increased, delaying OA development. At the later stages, P2X7 became over-activated, and the number of apoptotic cells increased, promoting OA development. We propose that the IRE1-mTOR-PERK signaling axis was involved in the regulation of autophagy inhibition and the induction of apoptosis. Our findings provide novel insights into the positive and preventative effects of exercise on OA, suggesting that the intensity and duration of exercise play a critical role. We also demonstrated that on a molecular level, P2X7 and its downstream pathways could be potential therapeutic targets for OA.

Keywords:  P2X7 receptor; autophagy; endoplasmic reticulum stress; inositol-requiring enzyme-1; mammalian target of rapamycin; osteoarthritis; protein kinase R-like endoplasmic reticulum kinase; treadmill exercise

DOI:  https://doi.org/10.3389/fcell.2021.695041
Front Cell Dev Biol. 2021 ;9 631413

Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression.

Bohan Xu, Linbin Zhou, Qishan Chen, Jianing Zhang, Lijuan Huang, Shasha Wang, Zhimin Ye, Xiangrong Ren, Yu Cai, Lasse Dahl Jensen, Weirong Chen, Xuri Li, Rong Ju.

  Retinal pigment epithelium (RPE), a postmitotic monolayer located between the neuroretina and choroid, supports the retina and is closely associated with vision loss diseases such as age-related macular degeneration (AMD) upon dysfunction. Although environmental stresses are known to play critical roles in AMD pathogenesis and the roles of other stresses have been well investigated, glucose deprivation, which can arise from choriocapillary flow voids, has yet to be fully explored. In this study, we examined the involvement of VEGFR2 in glucose deprivation-mediated cell death and the underlying mechanisms. We found that VEGFR2 levels are a determinant for RPE cell death, a critical factor for dry AMD, under glucose deprivation. RNA sequencing analysis showed that upon VEGFR2 knockdown under glucose starvation, endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are reduced. Consistently, VEGFR2 overexpression increased ER stress under the same condition. Although VEGFR2 was less expressed compared to EGFR1 and c-Met in RPE cells, it could elicit a higher level of ER stress induced by glucose starvation. Finally, downregulated VEGFR2 attenuated the oxidative stress and inflammatory factor expression, two downstream targets of ER stress. Our study, for the first time, has demonstrated a novel role of VEGFR2 in RPE cells under glucose deprivation, thus providing valuable insights into the mechanisms of AMD pathogenesis and suggesting that VEGFR2 might be a potential therapeutic target for AMD prevention, which may impede its progression.

Keywords:  ER stress; VEGFR2; advanced technology; eye diseases; glucose deprivation; translational vision science; visual development

DOI:  https://doi.org/10.3389/fcell.2021.631413
FEBS J. 2021 Jul 06.

Regulation of redox signaling in HIF1-dependent tumor angiogenesis.

Valeria Manuelli, Chiara Pecorari, Giuseppe Filomeni, Ester Zito.

  Angiogenesis is the process of blood vessel growth. The angiogenic switch consists of new blood vessel formation that, in carcinogenesis, can lead to the transition from a harmless cluster of dormant cells to a large tumorigenic mass with metastatic potential. Hypoxia, i.e. the scarcity of oxygen, is a hallmark of solid tumors to which they adapt by activating hypoxia-inducible factor-1 (HIF-1), a transcription factor triggering de novo angiogenesis. HIF-1 and the angiogenic molecules that are expressed upon its activation are modulated by redox status. Modulations of the redox environment can influence the angiogenesis signaling at different levels, thereby impinging on the angiogenic switch. This review provides a molecular overview of the redox-sensitive steps in angiogenic signaling, the main molecular players involved and their crosstalk with the unfolded protein response (UPR). New classes of inhibitors of these modulators which might act as antiangiogenic drugs in cancer are also discussed.

Keywords:  ER stress; ERO1; HIF-1; UPR; angiogenesis; hypoxia; metastasis

DOI:  https://doi.org/10.1111/febs.16110
Cell Immunol. 2021 Jun 30. pii: S0008-8749(21)00120-9. [Epub ahead of print]367 104401

ATF6 promotes liver fibrogenesis by regulating macrophage-derived interleukin-1α expression.

Quanrongzi Wang, Xinya Zhu, Zijian Li, Min Feng, Xisheng Liu.

  Macrophages contribute to liver fibrogenesis by the production of a large variety of cytokines. ATF6 is associated with the activation of macrophages. The present study aimed to investigate the role of ATF6 in the expression of macrophage-derived cytokines and liver fibrogenesis after acute liver injury. Following thioacetamide (TAA)-induced acute liver injury, the characteristics of the occurrence of liver fibrosis and the secretion of cytokines by macrophages were first described. Then, the role of various cytokines secreted by macrophages in activating hepatic stellate cells (HSCs) was tested in vitro. Finally, endoplasmic reticulum stress (ER-stress) signals in macrophages were detected following liver injury. siRNA was used to interfere with the expression of ATF6 in macrophages to verify the influence of ATF6 on cytokine expression and liver fibrogenesis after liver injury. A single intraperitoneal injection of TAA induced acute liver injury. The depletion of macrophages attenuated acute liver injury, while it inhibited liver fibrogenesis. During acute liver injury, macrophages secrete a variety of cytokines. Most of these cytokines promoted the activation of HSCs, but the effect of IL-1α was most significant. In the early stage of acute liver injury, ER-stress signals in macrophages were activated. Interference of ATF6 expression suppressed the secretion of cytokines by macrophages and attenuated liver fibrogenesis. Overall, in the early stage of acute liver injury, ATF6 signals promoted the expression of macrophage-derived cytokines to participate in liver fibrogenesis, and IL-1α exhibited the most significant role in promoting the activation of HSCs and liver fibrogenesis.

Keywords:  ATF6; Endoplasmic reticulum stress; Interleukin-1α; Liver fibrogenesis; Macrophages

DOI:  https://doi.org/10.1016/j.cellimm.2021.104401
Sci Rep. 2021 Jul 08. 11(1): 14161

Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide.

Nadja I Lorenz, Alina C M Sittig, Hans Urban, Anna-Luisa Luger, Anna L Engel, Christian Münch, Joachim P Steinbach, Michael W Ronellenfitsch.

The integrated stress response (ISR) is a central cellular adaptive program that is activated by diverse stressors including ER stress, hypoxia and nutrient deprivation to orchestrate responses via activating transcription factor 4 (ATF4). We hypothesized that ATF4 is essential for the adaptation of human glioblastoma (GB) cells to the conditions of the tumor microenvironment and is contributing to therapy resistance against chemotherapy. ATF4 induction in GB cells was modulated pharmacologically and genetically and investigated in the context of temozolomide treatment as well as glucose and oxygen deprivation. The relevance of the ISR was analyzed by cell death and metabolic measurements under conditions to approximate aspects of the GB microenvironment. ATF4 protein levels were induced by temozolomide treatment. In line, ATF4 gene suppressed GB cells (ATF4sh) displayed increased cell death and decreased survival after temozolomide treatment. Similar results were observed after treatment with the ISR inhibitor ISRIB. ATF4sh and ISRIB treated GB cells were sensitized to hypoxia-induced cell death. Our experimental study provides evidence for an important role of ATF4 for the adaptation of human GB cells to conditions of the tumor microenvironment characterized by low oxygen and nutrient availability and for the development of temozolomide resistance. Inhibiting the ISR in GB cells could therefore be a promising therapeutic approach.

DOI: https://doi.org/10.1038/s41598-021-93663-1
Cell Death Discov. 2021 Jun 29. 7(1): 152

OASIS/CREB3L1 is a factor that responds to nuclear envelope stress.

Yasunao Kamikawa, Atsushi Saito, Koji Matsuhisa, Masayuki Kaneko, Rie Asada, Yasunori Horikoshi, Satoshi Tashiro, Kazunori Imaizumi.

The nuclear envelope (NE) safeguards the genome and is pivotal for regulating genome activity as the structural scaffold of higher-order chromatin organization. NE had been thought as the stable during the interphase of cell cycle. However, recent studies have revealed that the NE can be damaged by various stresses such as mechanical stress and cellular senescence. These types of stresses are called NE stress. It has been proposed that NE stress is closely related to cellular dysfunctions such as genome instability and cell death. Here, we found that an endoplasmic reticulum (ER)-resident transmembrane transcription factor, OASIS, accumulates at damaged NE. Notably, the major components of nuclear lamina, Lamin proteins were depleted at the NE where OASIS accumulates. We previously demonstrated that OASIS is cleaved at the membrane domain in response to ER stress. In contrast, OASIS accumulates as the full-length form to damaged NE in response to NE stress. The accumulation to damaged NE is specific for OASIS among OASIS family members. Intriguingly, OASIS colocalizes with the components of linker of nucleoskeleton and cytoskeleton complexes, SUN2 and Nesprin-2 at the damaged NE. OASIS partially colocalizes with BAF, LEM domain proteins, and a component of ESCRT III, which are involved in the repair of ruptured NE. Furthermore, OASIS suppresses DNA damage induced by NE stress and restores nuclear deformation under NE stress conditions. Our findings reveal a novel NE stress response pathway mediated by OASIS.

DOI: https://doi.org/10.1038/s41420-021-00540-x