bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2023–06–25
six papers selected by
Matías Eduardo González Quiroz, Worker’s Hospital
  1. Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity.
  2. Unfolded protein response is involved in resistance to Neospora caninum infection via IRE1α-XBP1s-NOD2 Axis.
  3. HIF1α-dependent hypoxia response in myeloid cells requires IRE1α.
  4. Perturbation of endoplasmic reticulum proteostasis triggers tissue injury in the thyroid gland.
  5. ER stress and lipid imbalance drive embryonic cardiomyopathy in a human heart organoid model of pregestational diabetes.
  6. XBP1s gene of endoplasmic reticulum stress enhances proliferation and osteogenesis of human periodontal ligament cells.
  1. Front Immunol. 2023 ;14 1209588
    Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity.
    Felipe Flores-Santibañez, Sofie Rennen, Dominique Fernández, Clint De Nolf, Evelien Van De Velde, Sandra Gaete González, Camila Fuentes, Carolina Moreno, Diego Figueroa, Álvaro Lladser, Takao Iwawaki, María Rosa Bono, Sophie Janssens, Fabiola Osorio.
      In cancer, activation of the IRE1/XBP1s axis of the unfolded protein response (UPR) promotes immunosuppression and tumor growth, by acting in cancer cells and tumor infiltrating immune cells. However, the role of IRE1/XBP1s in dendritic cells (DCs) in tumors, particularly in conventional type 1 DCs (cDC1s) which are cellular targets in immunotherapy, has not been fully elucidated. Here, we studied the role of IRE1/XBP1s in subcutaneous B16/B78 melanoma and MC38 tumors by generating loss-of-function models of IRE1 and/or XBP1s in DCs or in cDC1s. Data show that concomitant deletion of the RNase domain of IRE1 and XBP1s in DCs and cDC1s does not influence the kinetics of B16/B78 and MC38 tumor growth or the effector profile of tumor infiltrating T cells. A modest effect is observed in mice bearing single deletion of XBP1s in DCs, which showed slight acceleration of melanoma tumor growth and dysfunctional T cell responses, however, this effect was not recapitulated in animals lacking XBP1 only in cDC1s. Thus, evidence presented here argues against a general pro-tumorigenic role of the IRE1/XBP1s pathway in tumor associated DC subsets.
    Keywords:  IRE1; XBP1; antitumor immune response; cDC1; dendritic cells; immunity; melanoma; unfolded protein response
    DOI:  https://doi.org/10.3389/fimmu.2023.1209588
  2. Parasitol Res. 2023 Jun 23.
    Unfolded protein response is involved in resistance to Neospora caninum infection via IRE1α-XBP1s-NOD2 Axis.
    Zhichao Sun, Xin Li, Xu Zhang, Yuru Wang, Pengtao Gong, Nan Zhang, Xichen Zhang, Xiaocen Wang, Jianhua Li.
      Neospora caninum, an intracellular protozoan parasite, causes neosporosis resulting in major losses in the livestock industry worldwide. However, no effective drugs or vaccines have been developed to control neosporosis. An in-depth study on the immune response against N. caninum could help to search for effective approaches to prevent and treat neosporosis. The host unfolded protein response (UPR) functions as a double-edged sword in several protozoan parasite infections, either to initiate immune responses or to help parasite survival. In this study, the roles of the UPR in N. caninum infection in vitro and in vivo were explored, and the mechanism of the UPR in resistance to N. caninum infection was analyzed. The results revealed that N. caninum triggered the UPR in mouse macrophages, such as the activation of the IRE1 and PERK branches, but not the ATF6 branch. Inhibition of the IRE1α-XBP1s branch increased the N. caninum number both in vitro and in vivo, while inhibition of the PERK branch did not affect the parasite number. Furthermore, inhibition of the IRE1α-XBP1s branch reduced the production of cytokines by inhibiting NOD2 signalling and its downstream NF-κB and MAPK pathways. Taken together, the results of this study suggest that the UPR is involved in the resistance of N. caninum infection via the IRE1α-XBP1s branch by regulating NOD2 and its downstream NF-κB and MAPK pathways to induce the production of inflammatory cytokines, which provides a new perspective for the research and development of anti-N. caninum drugs.
    Keywords:  IRE1α-XBP1s branch; N. caninum; NOD2; Peritoneal macrophages; Unfolded protein response
    DOI:  https://doi.org/10.1007/s00436-023-07902-7
  3. J Neuroinflammation. 2023 Jun 21. 20(1): 145
    HIF1α-dependent hypoxia response in myeloid cells requires IRE1α.
    Gaëlle Mawambo, Malika Oubaha, Yusuke Ichiyama, Guillaume Blot, Sergio Crespo-Garcia, Agnieszka Dejda, François Binet, Roberto Diaz-Marin, Christina Sawchyn, Mikhail Sergeev, Rachel Juneau, Randal J Kaufman, El Bachir Affar, Frédérick A Mallette, Ariel M Wilson, Przemyslaw Sapieha.
      Cellular adaptation to low oxygen tension triggers primitive pathways that ensure proper cell function. Conditions of hypoxia and low glucose are characteristic of injured tissues and hence successive waves of inflammatory cells must be suited to function under low oxygen tension and metabolic stress. While Hypoxia-Inducible Factor (HIF)-1α has been shown to be essential for the inflammatory response of myeloid cells by regulating the metabolic switch to glycolysis, less is known about how HIF1α is triggered in inflammation. Here, we demonstrate that cells of the innate immune system require activity of the inositol-requiring enzyme 1α (IRE1α/XBP1) axis in order to initiate HIF1α-dependent production of cytokines such as IL1β, IL6 and VEGF-A. Knockout of either HIF1α or IRE1α in myeloid cells ameliorates vascular phenotypes in a model of retinal pathological angiogenesis driven by sterile inflammation. Thus, pathways associated with ER stress, in partnership with HIF1α, may co-regulate immune adaptation to low oxygen.
    Keywords:  Angiogenesis; ER stress; HIF1α; Hypoxia; IRE1α; Inflammation; Microglia; Mononuclear phagocytes; Myeloid; Retina
    DOI:  https://doi.org/10.1186/s12974-023-02793-y
  4. JCI Insight. 2023 06 22. pii: e169937. [Epub ahead of print]8(12):
    Perturbation of endoplasmic reticulum proteostasis triggers tissue injury in the thyroid gland.
    Xiaohan Zhang, Crystal Young, Xiao-Hui Liao, Samuel Refetoff, Mauricio Torres, Yaron Tomer, Mihaela Stefan-Lifshitz, Hao Zhang, Dennis Larkin, Deyu Fang, Ling Qi, Peter Arvan.
      Defects in endoplasmic reticulum (ER) proteostasis have been linked to diseases in multiple organ systems. Here we examined the impact of perturbation of ER proteostasis in mice bearing thyrocyte-specific knockout of either HRD1 (to disable ER-associated protein degradation [ERAD]) or ATG7 (to disable autophagy) in the absence or presence of heterozygous expression of misfolded mutant thyroglobulin (the most highly expressed thyroid gene product, synthesized in the ER). Misfolding-inducing thyroglobulin mutations are common in humans but are said to yield only autosomal-recessive disease - perhaps because misfolded thyroglobulin protein might undergo disposal by ERAD or ER macroautophagy. We find that as single defects, neither ERAD, nor autophagy, nor heterozygous thyroglobulin misfolding altered circulating thyroxine levels, and neither defective ERAD nor defective autophagy caused any gross morphological change in an otherwise WT thyroid gland. However, heterozygous expression of misfolded thyroglobulin itself triggered significant ER stress and individual thyrocyte death while maintaining integrity of the surrounding thyroid epithelium. In this context, deficiency of ERAD (but not autophagy) resulted in patchy whole-follicle death with follicular collapse and degeneration, accompanied by infiltration of bone marrow-derived macrophages. Perturbation of thyrocyte ER proteostasis is thus a risk factor for both cell death and follicular demise.
    Keywords:  Cell Biology; Protein misfolding
    DOI:  https://doi.org/10.1172/jci.insight.169937
  5. bioRxiv. 2023 Jun 08. pii: 2023.06.07.544081. [Epub ahead of print]
    ER stress and lipid imbalance drive embryonic cardiomyopathy in a human heart organoid model of pregestational diabetes.
    Aleksandra Kostina, Yonatan R Lewis-Israeli, Mishref Abdelhamid, Mitchell A Gabalski, Brett D Volmert, Haley Lankerd, Amanda R Huang, Aaron H Wasserman, Todd Lydic, Christina Chan, Isoken Olomu, Aitor Aguirre.
      Congenital heart defects constitute the most common birth defect in humans, affecting approximately 1% of all live births. The incidence of congenital heart defects is exacerbated by maternal conditions, such as diabetes during the first trimester. Our ability to mechanistically understand these disorders is severely limited by the lack of human models and the inaccessibility to human tissue at relevant stages. Here, we used an advanced human heart organoid model that recapitulates complex aspects of heart development during the first trimester to model the effects of pregestational diabetes in the human embryonic heart. We observed that heart organoids in diabetic conditions develop pathophysiological hallmarks like those previously reported in mouse and human studies, including ROS-mediated stress and cardiomyocyte hypertrophy, among others. Single cell RNA-seq revealed cardiac cell type specific-dysfunction affecting epicardial and cardiomyocyte populations, and suggested alterations in endoplasmic reticulum function and very long chain fatty acid lipid metabolism. Confocal imaging and LC-MS lipidomics confirmed our observations and showed that dyslipidemia was mediated by fatty acid desaturase 2 (FADS2) mRNA decay dependent on IRE1-RIDD signaling. We also found that the effects of pregestational diabetes could be reversed to a significant extent using drug interventions targeting either IRE1 or restoring healthy lipid levels within organoids, opening the door to new preventative and therapeutic strategies in humans.
    DOI:  https://doi.org/10.1101/2023.06.07.544081
  6. Tissue Cell. 2023 Jun 13. pii: S0040-8166(23)00127-1. [Epub ahead of print]83 102139
    XBP1s gene of endoplasmic reticulum stress enhances proliferation and osteogenesis of human periodontal ligament cells.
    Ziwei Cui, Ruoshan Qin, Jianbao Feng, Yuan Liu, Xiongtao Zhou, Xiaodong Qin, Yanmin Li, Zhidong Zhang, Xiangyi He.
       BACKGROUND: The endoplasmic reticulum stress (ERS) pathway, inositol-requiring enzyme-1 alpha-X-box binding protein-1 (IRE1α-XBP1), has been considered as a critical factor of human periodontal ligament cells (hPDLCs) in proliferation and osteogenesis. This study aimed to explore the effect and mechanism of XBP1s, which was cleaved by IRE1α on the proliferation and osteogenesis of hPDLCs.
    METHODS: ERS model was induced by tunicamycin (TM); cell proliferation was assessed by CCK-8 assay; pLVX-XBP1s-hPDLCs cell line was established by lentivirus infaction; expression of ERS-related protein including eIF2α, GRP78, ATF4 and XBP1s, autophagy-related P62 and LC3, and apoptosis-related Bcl-2 and Caspase-3 were detected by Western Blot; expression of osteogenic genes was detected by RT-qPCR, and senescence of hPDLCs was explored by β-galactosidase staining. Furthermore, the interaction between XBP1s and human bone morphogenetic protein 2 (BMP2) was examined by immunofluorescence antibody test (IFAT).
    RESULTS: The results showed an increase in proliferation of hPDLCs from 0 to 24 h when ERS was induced by TM treatment (P < 0.05). XBP1s overexpression induced hPDLCs proliferation, upgraded autophagy and degraded apoptosis significantly (P < 0.05). In pLVX-XBP1s-hPDLCs, the ratio of senescent cells was markedly decreased after several passages (P < 0.05); After infection with pLVX-BMP2 lentiviral supernatant, IFAT result showed that XBP1s and BMP2 well co-located in the cytoplasm of pLVX-XBP1s-hPDLCs and PERK-ATF4 ERS branch was activated, meanwhile, there were obviously more mineralized nodules and mRNA expression of osteogenesis-related genes was continually up-regulated (P < 0.05).
    CONCLUSIONS: XBP1s promotes the proliferation via regulating the autophagy and apoptosis, and enhances expression of osteogenic genes in hPDLCs. The mechanisms in this regard need exploring further for periodontal tissue regeneration, functionalization and clinical applications.
    Keywords:  Apoptosis; Autophagy; Endoplasmic reticulum stress; Human periodontal ligament cells; Osteogenesis
    DOI:  https://doi.org/10.1016/j.tice.2023.102139
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