bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022–02–27
thirteen papers selected by
Susan Logue, University of Manitoba
  1. Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression.
  2. Stress-induced tyrosine phosphorylation of RtcB modulates IRE1 activity and signaling outputs.
  3. Endoplasmic Reticulum Stress in Colonic Mucosa of Ulcerative Colitis Patients Is Mediated by PERK and IRE1 Pathway Activation.
  4. A lipid viewpoint in the plant endoplasmic reticulum stress response.
  5. Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma.
  6. IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma.
  7. Targeting EDEM protects against ER stress and improves development and survival in C. elegans.
  8. TIMP2 mediates endoplasmic reticulum stress contributing to sepsis-induced acute kidney injury.
  9. Neutrophils Contribute to ER Stress in Lung Epithelial Cells in the Pristane-Induced Diffuse Alveolar Hemorrhage Mouse Model.
  10. ER-phagy: mechanisms, regulation and diseases connected to the lysosomal clearance of the endoplasmic reticulum.
  11. How Cells Deal with the Fluctuating Environment: Autophagy Regulation under Stress in Yeast and Mammalian Systems.
  12. A DNA repair-independent role for alkyladenine DNA glycosylase in alkylation-induced unfolded protein response.
  13. The role of endoplasmic reticulum stress in the MHC class I antigen presentation pathway of dendritic cells.
  1. EMBO Mol Med. 2022 Feb 22. e15344
    Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression.
    Zehra Yildirim, Sabyasachi Baboo, Syed M Hamid, Asli E Dogan, Ozlem Tufanli, Sabrina Robichaud, Christina Emerton, Jolene K Diedrich, Hasan Vatandaslar, Fotis Nikolos, Yanghong Gu, Takao Iwawaki, Elizabeth Tarling, Mireille Ouimet, David L Nelson, John R Yates, Peter Walter, Ebru Erbay.
      Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring enzyme-1 (IRE1), an ER-resident stress-sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggests IRE1 inhibition as a promising new way to counteract atherosclerosis.
    Keywords:  ER stress; atherosclerosis; cholesterol homeostasis; efferocytosis; translational regulation
    DOI:  https://doi.org/10.15252/emmm.202115344
  2. Life Sci Alliance. 2022 May;pii: e202201379. [Epub ahead of print]5(5):
    Stress-induced tyrosine phosphorylation of RtcB modulates IRE1 activity and signaling outputs.
    Alexandra Papaioannou, Federica Centonze, Alice Metais, Marion Maurel, Luc Negroni, Matías Gonzalez-Quiroz, Sayyed Jalil Mahdizadeh, Gabriella Svensson, Ensieh Zare, Alice Blondel, Albert C Koong, Claudio Hetz, Rémy Pedeux, Michel L Tremblay, Leif A Eriksson, Eric Chevet.
      ER stress is mediated by three sensors and the most evolutionary conserved IRE1α signals through its cytosolic kinase and endoribonuclease (RNase) activities. IRE1α RNase activity can either catalyze the initial step of XBP1 mRNA unconventional splicing or degrade a number of RNAs through regulated IRE1-dependent decay. Until now, the biochemical and biological outputs of IRE1α RNase activity have been well documented; however, the precise mechanisms controlling whether IRE1α signaling is adaptive or pro-death (terminal) remain unclear. We investigated those mechanisms and hypothesized that XBP1 mRNA splicing and regulated IRE1-dependent decay activity could be co-regulated by the IRE1α RNase regulatory network. We identified that RtcB, the tRNA ligase responsible for XBP1 mRNA splicing, is tyrosine-phosphorylated by c-Abl and dephosphorylated by PTP1B. Moreover, we show that the phosphorylation of RtcB at Y306 perturbs RtcB interaction with IRE1α, thereby attenuating XBP1 mRNA splicing. Our results demonstrate that the IRE1α RNase regulatory network is dynamically fine-tuned by tyrosine kinases and phosphatases upon various stresses and that the extent of RtcB tyrosine phosphorylation determines cell adaptive or death outputs.
    DOI:  https://doi.org/10.26508/lsa.202201379
  3. Mediators Inflamm. 2022 ;2022 6049500
    Endoplasmic Reticulum Stress in Colonic Mucosa of Ulcerative Colitis Patients Is Mediated by PERK and IRE1 Pathway Activation.
    Bruno Lima Rodrigues, Isabella Dotti, Lívia Bitencourt Pascoal, Joseane Morari, Miriam Esteller, Andressa Coope, Maria de Lourdes Setsuko Ayrizono, Azucena Salas, Raquel Franco Leal.
      Ulcerative colitis (UC) is characterized by a chronic overproduction of proinflammatory cytokines. During an acute phase, the endoplasmic reticulum (ER) is overloaded and the protein folding process is impaired, a condition named ER stress. This state induces a response (unfolded protein response (UPR)), initiated by the activation of IRE1/Xbp-1, PERK/eIF2α, and ATF6 pathways, which has previously been linked to intestinal inflammation in experimental models. ER stress and UPR activation trigger the activation of proinflammatory, autophagy, and apoptosis genes, in addition to promoting protein degradation. Therefore, the goal of this study was to evaluate the activation of ER stress and UPR in colonic mucosa of UC patients. Patient and Methods. Transcriptional analysis of ER stress- and UPR-related genes was performed by qPCR from intestinal mucosa of patients with UC. We also performed in situ hybridization (ISH) and immunohistochemistry (IHQ) of PERK/eIF2α and IRE1/Xbp-1 pathways and UPR-related chaperones. Results. We first evaluated inflammatory genes via qPCR, and we observed that all analyzed proinflammatory transcripts were upregulated in UC patients. ISH and IHQ images showed that ER stress is activated via PERK/eIF2α and IRE1/Xbp-1 pathways not only in intestinal epithelial cells but also in cells of the lamina propria of UC colonic mucosa. Transcriptional analysis confirmed that EIF2AK3 was upregulated in UC patients. UPR-related genes, such as ATF3, STC2, and DDIT3, along with the chaperones and cochaperones DNAJC3, CALR, HSP90B1, and HSPA5, were also upregulated in UC patients. In addition, we observed that proapoptotic and autophagy genes (Bax and ATG6L1, respectively) were also upregulated. Conclusion. Our results suggest that ER stress and UPR are indeed activated in UC patients and this may contribute to the chronic inflammatory process seen in UC. The increased apoptosis and autophagy markers further support the activation of these findings once they are activated to counterbalance tissue damage. These findings provide new insights into the molecular mechanisms that maintain UC activity and open new possibilities to attenuate intestinal inflammation.
    DOI:  https://doi.org/10.1155/2022/6049500
  4. J Exp Bot. 2022 Feb 23. pii: erac063. [Epub ahead of print]
    A lipid viewpoint in the plant endoplasmic reticulum stress response.
    Kazue Kanehara, Yueh Cho, Chao-Yuan Yu.
      Organisms including humans seem to be ever exposed to various changes, which often have undesirable effects, referred to as stress. Keeping up with the constant changes, eukaryotic cells may have evolved a number of relevant cellular processes, such as the endoplasmic reticulum (ER) stress response. Due to presumably intimate links between human diseases and the ER function, the ER stress response has been extensively investigated in the various organisms for a few decades. Now we are able to have a picture of the molecular mechanisms of the ER stress response, one of which, the unfolded protein response (UPR), is highly conserved among yeasts, mammals, higher plants, and green algae. In this review, we attempt to highlight the plant UPR from the perspective of lipids, especially membrane phospholipids. Phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) are the most abundant membrane phospholipids in eukaryotic cells. The ratio of PtdCho to PtdEtn and unsaturation of fatty acyl tails in both phospholipids are critical factors for the UPR, but the biosynthetic pathway responsible for PtdCho and PtdEtn are distinct in animals and plants. We discuss the plant UPR in comparison with the system in yeasts and animals in the context of membrane phospholipids.
    Keywords:   Arabidopsis thaliana ; INOSITOL-REQUIRING ENZYME1 (IRE1); endoplasmic reticulum (ER) stress; fatty acid; inositol; lipid; membrane saturation; phospholipids; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1093/jxb/erac063
  5. Cells. 2022 Feb 11. pii: 632. [Epub ahead of print]11(4):
    Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma.
    Jaafar Khaled, Maria Kopsida, Hans Lennernäs, Femke Heindryckx.
      Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a vast need for understanding underlying mechanisms that contribute to drug resistance and for developing therapeutic strategies that would overcome this. The rapid proliferation of tumor cells, in combination with a highly inflammatory microenvironment, causes a chronic increase of protein synthesis in different hepatic cell populations. This leads to an intensified demand of protein folding, which inevitably causes an accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER). This process is called ER stress and triggers the unfolded protein response (UPR) in order to restore protein synthesis or-in the case of severe or prolonged ER stress-to induce cell death. Interestingly, the three different arms of the ER stress signaling pathways have been shown to drive chemoresistance in several tumors and could therefore form a promising therapeutic target. This review provides an overview of how ER stress and activation of the UPR contributes to drug resistance in HCC.
    Keywords:  anthracyclins; drug resistance; endoplasmic reticulum stress; liver cancer; transarterial chemoembolization; tumor microenvironment; unfolded protein response
    DOI:  https://doi.org/10.3390/cells11040632
  6. Discov Oncol. 2021 Nov 30. 12(1): 57
    IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma.
    Keita Sasa, Tsuyoshi Saito, Taisei Kurihara, Nobuhiko Hasegawa, Kei Sano, Daisuke Kubota, Keisuke Akaike, Taketo Okubo, Takuo Hayashi, Tatsuya Takagi, Takashi Yao, Muneaki Ishijima, Yoshiyuki Suehara.
      Osteosarcoma (OS) is the most common primary malignant bone tumor. However, the therapeutic results of the advanced cases at the first visit were still extremely poor. Therefore, more effective therapeutic options based on molecular profiling of OS are needed. In this study, we investigated the functions of endoplasmic reticulum (ER) stress activities in OS and elucidated whether ER stress inhibitors could exert antitumor effects. The expression of 84 key genes associated with unfolded protein response (UPR) was assessed in four OS cells (143B, MG63, U2OS and KHOS) by RT2 Profiler PCR Arrays. Based on results, we performed both siRNA and inhibitor assays focusing on IRE1α-XBP1 and PERK pathways. All OS cell lines showed resistance to PERK inhibitors. Furthermore, ATF4 and EIF2A inhibition by siRNA did not affect the survival of OS cell lines. On the other hand, IRE1α-XBP1 inhibition by toyocamycin suppressed OS cell growth (IC50: < 0.075 μM) and cell viability was suppressed in all OS cell lines by silencing XBP1 expression. The expression of XBP1s and XBP1u in OS cell lines and OS surgical samples were confirmed using qPCR. In MG63 and U2OS, toyocamycin decreased the expression level of XBP1s induced by tunicamycin. On the other hand, in 143B and KHOS, stimulation by toyocamycin did not clearly change the expression level of XBP1s induced by tunicamycin. However, morphological apoptotic changes and caspase activation were observed in these two cell lines. Inhibition of the IRE1α-XBP1s pathway is expected to be a promising new target for OS.
    Keywords:  ER stress; IRE1α-XBP1 pathway; Osteosarcoma
    DOI:  https://doi.org/10.1007/s12672-021-00453-2
  7. PLoS Genet. 2022 Feb 22. 18(2): e1010069
    Targeting EDEM protects against ER stress and improves development and survival in C. elegans.
    Simona Ghenea, Marioara Chiritoiu, Robi Tacutu, Antonio Miranda-Vizuete, Stefana Maria Petrescu.
      EDEM-1, EDEM-2 and EDEM-3 are key players for the quality control of newly synthesized proteins in the endoplasmic reticulum (ER) by accelerating disposal and degradation of misfolded proteins through ER Associated Degradation (ERAD). Although many previous studies reported the role of individual ERAD components especially in cell-based systems, still little is known about the consequences of ERAD dysfunction under physiological and ER stress conditions in the context of a multicellular organism. Here we report the first individual and combined characterization and functional interplay of EDEM proteins in Caenorhabditis elegans using single, double, and triple mutant combinations. We found that EDEM-2 has a major role in the clearance of misfolded proteins from ER under physiological conditions, whereas EDEM-1 and EDEM-3 roles become prominent under acute ER stress. In contrast to SEL-1 loss, the loss of EDEMs in an intact organism induces only a modest ER stress under physiological conditions. In addition, chronic impairment of EDEM functioning attenuated both XBP-1 activation and up-regulation of the stress chaperone GRP78/BiP, in response to acute ER stress. We also show that pre-conditioning to EDEM loss in acute ER stress restores ER homeostasis and promotes survival by activating ER hormesis. We propose a novel role for EDEM in fine-tuning the ER stress responsiveness that affects ER homeostasis and survival.
    DOI:  https://doi.org/10.1371/journal.pgen.1010069
  8. FASEB J. 2022 Apr;36(4): e22228
    TIMP2 mediates endoplasmic reticulum stress contributing to sepsis-induced acute kidney injury.
    Nanhui Jiang, Rong Huang, Jiahao Zhang, Dongxue Xu, Tianlong Li, Zhongyi Sun, Lianjiu Su, Zhiyong Peng.
      Tissue inhibitor of metalloproteinase 2 (TIMP2) has been recognized as an important biomarker for predicting acute kidney injury (AKI) because of its involvement in the process of inflammation and apoptosis in septic AKI. Endoplasmic reticulum (ER) stress, a condition of disrupted ER homeostasis, is implicated in multiple pathophysiological processes, including kidney disease. Herein, we investigated the correlation between ER stress and septic AKI and further explored how TIMP2 regulated ER stress-mediated apoptosis. To assess the role of TIMP2 in sepsis-induced AKI, we used a cecal ligation and puncture (CLP) model in mice with tubule-specific deficiency of TIMP2 (Ksp-Cre/TIMP2flox / flox ) and their wild-type counterparts. Compared to the wild-type mice, TIMP2-deficient mice demonstrated lower serum creatinine levels and decreased ER stress-mediated apoptosis when subjected to CLP. Interestingly, in human kidney (HK-2) cells, overexpression of TIMP2 caused ER stress, whereas TIMP2 knockdown attenuated lipopolysaccharide-induced ER stress and apoptosis. TIMP2 interacted with the binding immunoglobulin protein, an ER chaperone, and facilitates its extracellular secretion, thereby triggering ER stress. This study identified that the deletion of TIMP2 in mouse tubules mitigated sepsis-induced AKI by inhibiting ER stress-mediated apoptosis, which might be a potential therapeutic strategy to alleviate renal injury.
    Keywords:  acute kidney injury (AKI); apoptosis; endoplasmic reticulum stress (ER stress); sepsis; tissue inhibitor of metalloproteinase 2 (TIMP2)
    DOI:  https://doi.org/10.1096/fj.202101555RR
  9. Front Immunol. 2022 ;13 790043
    Neutrophils Contribute to ER Stress in Lung Epithelial Cells in the Pristane-Induced Diffuse Alveolar Hemorrhage Mouse Model.
    Gantsetseg Tumurkhuu, Duygu Ercan Laguna, Richard E Moore, Jorge Contreras, Gabriela De Los Santos, Luisa Akaveka, Erica N Montano, Yizhou Wang, Mariko Ishimori, Swamy Venuturupalli, Lindsy J Forbess, Barry R Stripp, Daniel J Wallace, Caroline A Jefferies.
      Diffuse alveolar hemorrhage (DAH), although rare, is a life-threatening complication of systemic lupus erythematosus (SLE). Little is known about the pathophysiology of DAH in humans, although increasingly neutrophils, NETosis and inflammatory monocytes have been shown to play an important role in the pristane-induced model of SLE which develops lung hemorrhage and recapitulates many of the pathologic features of human DAH. Using this experimental model, we asked whether endoplasmic reticulum (ER) stress played a role in driving the pathology of pulmonary hemorrhage and what role infiltrating neutrophils had in this process. Analysis of lung tissue from pristane-treated mice showed genes associated with ER stress and NETosis were increased in a time-dependent manner and reflected the timing of CD11b+Ly6G+ neutrophil accumulation in the lung. Using precision cut lung slices from untreated mice we observed that neutrophils isolated from the peritoneal cavity of pristane-treated mice could directly induce the expression of genes associated with ER stress, namely Chop and Bip. Mice which had myeloid-specific deletion of PAD4 were generated and treated with pristane to assess the involvement of PAD4 and PAD4-dependent NET formation in pristane-induced lung inflammation. Specific deletion of PAD4 in myeloid cells resulted in decreased expression of ER stress genes in the pristane model, with accompanying reduction in IFN-driven genes and pathology. Lastly, coculture experiments of human neutrophils and human lung epithelial cell line (BEAS-2b) showed neutrophils from SLE patients induced significantly more ER stress and interferon-stimulated genes in epithelial cells compared to healthy control neutrophils. These results support a pathogenic role of neutrophils and NETs in lung injury during pristane-induced DAH through the induction of ER stress response and suggest that overactivation of neutrophils in SLE and NETosis may underlie development of DAH.
    Keywords:  ER stress; NEtosis; diffuse alveolar hemorrhage (DAH); lung inflammation; neutrophil (PMN); systemic lupus erythematosus (SLE)
    DOI:  https://doi.org/10.3389/fimmu.2022.790043
  10. Physiol Rev. 2022 Feb 21.
    ER-phagy: mechanisms, regulation and diseases connected to the lysosomal clearance of the endoplasmic reticulum.
    Fulvio Reggiori, Maurizio Molinari.
      ER-phagy (reticulo-phagy) defines the degradation of portions of the endoplasmic reticulum (ER) within lysosomes or vacuoles. It is part of the self-digestion (i.e., auto-phagic) programs recycling cytoplasmic material and organelles, which rapidly mobilize metabolites in cells confronted with nutrient shortage. Moreover, selective clearance of ER subdomains participates to the control of ER size and activity during ER stress, the re-establishment of ER homeostasis after ER stress resolution and the removal of ER parts, in which aberrant and potentially cytotoxic material has been segregated. ER-phagy relies on the individual and/or concerted activation of the ER-phagy receptors, ER peripheral or integral membrane proteins that share the presence of LC3/Atg8-binding motifs in their cytosolic domains. ER-phagy involves the physical separation of portions of the ER from the bulk ER network, and their delivery to the endolysosomal/vacuolar catabolic district. This last step is accomplished by a variety of mechanisms including macro-ER-phagy (in which ER fragments are sequestered by double-membrane autophagosomes that eventually fuse with lysosomes/vacuoles), micro-ER-phagy (in which ER fragments are directly engulfed by endosomes/lysosomes/vacuoles), or direct fusion of ER-derived vesicles with lysosomes/vacuoles. ER-phagy is dysfunctional in specific human diseases and its regulators are subverted by pathogens, highlighting its crucial role for cell and organism life.
    Keywords:  Autophagy; Disease; ER-phagy; Endoplasmic Reticulum; Lysosomal degradation
    DOI:  https://doi.org/10.1152/physrev.00038.2021
  11. Antioxidants (Basel). 2022 Feb 02. pii: 304. [Epub ahead of print]11(2):
    How Cells Deal with the Fluctuating Environment: Autophagy Regulation under Stress in Yeast and Mammalian Systems.
    Yuchen Lei, Yuxiang Huang, Xin Wen, Zhangyuan Yin, Zhihai Zhang, Daniel J Klionsky.
      Eukaryotic cells frequently experience fluctuations of the external and internal environments, such as changes in nutrient, energy and oxygen sources, and protein folding status, which, after reaching a particular threshold, become a type of stress. Cells develop several ways to deal with these various types of stress to maintain homeostasis and survival. Among the cellular survival mechanisms, autophagy is one of the most critical ways to mediate metabolic adaptation and clearance of damaged organelles. Autophagy is maintained at a basal level under normal growing conditions and gets stimulated by stress through different but connected mechanisms. In this review, we summarize the advances in understanding the autophagy regulation mechanisms under multiple types of stress including nutrient, energy, oxidative, and ER stress in both yeast and mammalian systems.
    Keywords:  ER stress; autophagy; energy stress; nutrient stress; oxidative stress; regulation
    DOI:  https://doi.org/10.3390/antiox11020304
  12. Proc Natl Acad Sci U S A. 2022 Mar 01. pii: e2111404119. [Epub ahead of print]119(9):
    A DNA repair-independent role for alkyladenine DNA glycosylase in alkylation-induced unfolded protein response.
    Larissa Milano, Clara F Charlier, Rafaela Andreguetti, Thomas Cox, Eleanor Healing, Marcos P Thomé, Ruan M Elliott, Leona D Samson, Jean-Yves Masson, Guido Lenz, João Antonio P Henriques, Axel Nohturfft, Lisiane B Meira.
      Alkylating agents damage DNA and proteins and are widely used in cancer chemotherapy. While cellular responses to alkylation-induced DNA damage have been explored, knowledge of how alkylation affects global cellular stress responses is sparse. Here, we examined the effects of the alkylating agent methylmethane sulfonate (MMS) on gene expression in mouse liver, using mice deficient in alkyladenine DNA glycosylase (Aag), the enzyme that initiates the repair of alkylated DNA bases. MMS induced a robust transcriptional response in wild-type liver that included markers of the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) known to be controlled by XBP1, a key UPR effector. Importantly, this response is significantly reduced in the Aag knockout. To investigate how AAG affects alkylation-induced UPR, the expression of UPR markers after MMS treatment was interrogated in human glioblastoma cells expressing different AAG levels. Alkylation induced the UPR in cells expressing AAG; conversely, AAG knockdown compromised UPR induction and led to a defect in XBP1 activation. To verify the requirements for the DNA repair activity of AAG in this response, AAG knockdown cells were complemented with wild-type Aag or with an Aag variant producing a glycosylase-deficient AAG protein. As expected, the glycosylase-defective Aag does not fully protect AAG knockdown cells against MMS-induced cytotoxicity. Remarkably, however, alkylation-induced XBP1 activation is fully complemented by the catalytically inactive AAG enzyme. This work establishes that, besides its enzymatic activity, AAG has noncanonical functions in alkylation-induced UPR that contribute to cellular responses to alkylation.
    Keywords:  DNA damage; ER stress; alkylating agents; base excision repair; unfolded protein response
    DOI:  https://doi.org/10.1073/pnas.2111404119
  13. Mol Immunol. 2022 Feb 17. pii: S0161-5890(22)00028-1. [Epub ahead of print]144 44-48
    The role of endoplasmic reticulum stress in the MHC class I antigen presentation pathway of dendritic cells.
    Bénédicte Manoury, Lucie Maisonneuve, Katrina Podsypanina.
      Dendritic cells (DCs) have the unique capacity to link innate to adaptive immunity. While most cells that express major histocompatibility (MHC) molecules are able to present antigens to activated T cells, DCs possess the means for presenting antigens to naïve T cells, and, as such, are able to instruct T cells to initiate immune response. There are two cascades of events necessary for DCs to start their instructive function. First, DCs enzymatically process proteins to make T cells recognize an antigen as unique peptide-MHC complexes. Second, DCs provide secretory cytokines and co-stimulatory functions for T cells to respond to this antigen. Thus, the compartments for protein degradation and for protein synthesis are central to DC function. The endoplasmic reticulum (ER), a vast network of membranes and vesicles, connects these compartments and helps modulate DC-specific performance, such as antigen capture and presentation. However, while the health of ER appears relevant for DC function, the intersection between ER stress and antigen presentation remains to be explored.
    Keywords:  Dendritic cells; Endoplasmic reticulum stress; IRE1α; MHCI antigen presentation
    DOI:  https://doi.org/10.1016/j.molimm.2022.02.007
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