bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021‒10‒24
ten papers selected by
Susan Logue
University of Manitoba

  1. Nat Immunol. 2021 Oct 22.
      Tumor-associated macrophages (TAMs) display pro-tumorigenic phenotypes for supporting tumor progression in response to microenvironmental cues imposed by tumor and stromal cells. However, the underlying mechanisms by which tumor cells instruct TAM behavior remain elusive. Here, we uncover that tumor-cell-derived glucosylceramide stimulated unconventional endoplasmic reticulum (ER) stress responses by inducing reshuffling of lipid composition and saturation on the ER membrane in macrophages, which induced IRE1-mediated spliced XBP1 production and STAT3 activation. The cooperation of spliced XBP1 and STAT3 reinforced the pro-tumorigenic phenotype and expression of immunosuppressive genes. Ablation of XBP1 expression with genetic manipulation or ameliorating ER stress responses by facilitating LPCAT3-mediated incorporation of unsaturated lipids to the phosphatidylcholine hampered pro-tumorigenic phenotype and survival in TAMs. Together, we uncover the unexpected roles of tumor-cell-produced lipids that simultaneously orchestrate macrophage polarization and survival in tumors via induction of ER stress responses and reveal therapeutic targets for sustaining host antitumor immunity.
  2. FASEB J. 2021 Nov;35(11): e21990
      Eukaryotic initiation factor 2A (eIF2A) is a 65 kDa protein that functions in minor initiation pathways, which affect the translation of only a subset of messenger ribonucleic acid (mRNAs), such as internal ribosome entry site (IRES)-containing mRNAs and/or mRNAs harboring upstream near cognate/non-AUG start codons. These non-canonical initiation events are important for regulation of protein synthesis during cellular development and/or the integrated stress response. Selective eIF2A knockdown in cellular systems significantly inhibits translation of such mRNAs, which rely on alternative initiation mechanisms for their translation. However, there exists a gap in our understanding of how eIF2A functions in mammalian systems in vivo (on the organismal level) and ex vivo (in cells). Here, using an eIF2A-knockout (KO) mouse model, we present evidence implicating eIF2A in the biology of aging, metabolic syndrome and central tolerance. We discovered that eIF2A-KO mice have reduced life span and that eIF2A plays an important role in maintenance of lipid homeostasis, the control of glucose tolerance, insulin resistance and also reduces the abundance of B lymphocytes and dendritic cells in the thymic medulla of mice. We also show the eIF2A KO affects male and female mice differently, suggesting that eIF2A may affect sex-specific pathways. Interestingly, our experiments involving pharmacological induction of endoplasmic reticulum (ER) stress with tunicamycin did not reveal any substantial difference between the response to ER stress in eIF2A-KO and wild-type mice. The identification of eIF2A function in the development of metabolic syndrome bears promise for the further identification of specific eIF2A targets responsible for these changes.
    Keywords:  ER stress; eukaryotic initiation factor 2A (eIF2A); life span; lipid homeostasis; metabolic syndrome
  3. Front Cell Dev Biol. 2021 ;9 740653
      The endoplasmic reticulum quality control (ERQC) system, including endoplasmic reticulum-associated degradation (ERAD), the unfolded protein response (UPR), and autophagy, presides over cellular protein secretion and maintains proteostasis in mammalian cells. As part of the immune system, a variety of proteins are synthesized and assembled correctly for the development, activation, and differentiation of immune cells, such as dendritic cells (DCs), macrophages, myeloid-derived-suppressor cells (MDSCs), B lymphocytes, T lymphocytes, and natural killer (NK) cells. In this review, we emphasize the role of the ERQC in these immune cells, and also discuss how the imbalance of ER homeostasis affects the immune response, thereby suggesting new therapeutic targets for immunotherapy.
    Keywords:  ERAD; ERQC; UPR; autophagy; immune cell
  4. Int J Mol Sci. 2021 Oct 13. pii: 11049. [Epub ahead of print]22(20):
      The sigma-1 receptor (S1R) is a highly conserved transmembrane protein highly enriched in mitochondria-associated endoplasmic reticulum (ER) membranes, where it interacts with several partners involved in ER-mitochondria Ca2+ transfer, activation of the ER stress pathways, and mitochondria function. We characterized a new S1R deficient zebrafish line and analyzed the impact of S1R deficiency on visual, auditory and locomotor functions. The s1r+25/+25 mutant line showed impairments in visual and locomotor functions compared to s1rWT. The locomotion of the s1r+25/+25 larvae, at 5 days post fertilization, was increased in the light and dark phases of the visual motor response. No deficit was observed in acoustic startle response. A critical role of S1R was shown in ER stress pathways and mitochondrial activity. Using qPCR to analyze the unfolded protein response genes, we observed that loss of S1R led to decreased levels of IRE1 and PERK-related effectors and increased over-expression of most of the effectors after a tunicamycin challenge. Finally, S1R deficiency led to alterations in mitochondria bioenergetics with decreased in basal, ATP-linked and non-mitochondrial respiration and following tunicamycin challenge. In conclusion, this new zebrafish model confirmed the importance of S1R activity on ER-mitochondria communication. It will be a useful tool to further analyze the physiopathological roles of S1R.
    Keywords:  ER stress; mitochondria bioenergetics; phenotyping; sigma-1 receptor; zebrafish
  5. Front Endocrinol (Lausanne). 2021 ;12 749879
      β-cell ER stress plays an important role in β-cell dysfunction and death during the pathogenesis of diabetes. Proinsulin misfolding is regarded as one of the primary initiating factors of ER stress and unfolded protein response (UPR) activation in β-cells. Here, we found that the ER stress sensor inositol-requiring enzyme 1α (IRE1α) was activated in the Akita mice, a mouse model of mutant insulin gene-induced diabetes of youth (MIDY), a monogenic diabetes. Normalization of IRE1α RNase hyperactivity by pharmacological inhibitors significantly ameliorated the hyperglycemic conditions and increased serum insulin levels in Akita mice. These benefits were accompanied by a concomitant protection of functional β-cell mass, as shown by the suppression of β-cell apoptosis, increase in mature insulin production and reduction of proinsulin level. At the molecular level, we observed that the expression of genes associated with β-cell identity and function was significantly up-regulated and ER stress and its associated inflammation and oxidative stress were suppressed in islets from Akita mice treated with IRE1α RNase inhibitors. This study provides the evidence of the in vivo efficacy of IRE1α RNase inhibitors in Akita mice, pointing to the possibility of targeting IRE1α RNase as a therapeutic direction for the treatment of diabetes.
    Keywords:  Beta cell failure; ER stress; Ire1alpha; Ire1alpha inhibition; beta cell protection; monogenic diabetes; proinsulin misfolding; unfolded protein response
  6. Cell Death Dis. 2021 Oct 18. 12(11): 960
      Aberrant activation of endoplasmic reticulum (ER) stress by extrinsic and intrinsic factors contributes to tumorigenesis and resistance to chemotherapies in various cancer types. Our previous studies have shown that the downregulation of PHLPP, a novel family of Ser/Thr protein phosphatases, promotes tumor initiation, and progression. Here we investigated the functional interaction between the ER stress and PHLPP expression in colon cancer. We found that induction of ER stress significantly decreased the expression of PHLPP proteins through a proteasome-dependent mechanism. Knockdown of PHLPP increased the phosphorylation of eIF2α as well as the expression of autophagy-associated genes downstream of the eIF2α/ATF4 signaling pathway. In addition, results from immunoprecipitation experiments showed that PHLPP interacted with eIF2α and this interaction was enhanced by ER stress. Functionally, knockdown of PHLPP improved cell survival under ER stress conditions, whereas overexpression of a degradation-resistant mutant PHLPP1 had the opposite effect. Taken together, our studies identified ER stress as a novel mechanism that triggers PHLPP downregulation; and PHLPP-loss promotes chemoresistance by upregulating the eIF2α/ATF4 signaling axis in colon cancer cells.
  7. Cells. 2021 Oct 13. pii: 2730. [Epub ahead of print]10(10):
      Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and liver injury. The present study aimed to investigate if mechanistic target of rapamycin complex 1 (mTORC1) plays a role in FFA-induced organelle dysfunction, thereby contributing to the development of ALD. Cell studies were conducted to define the causal role and underlying mechanism of FFA-activated mTORC1 signaling in hepatocellular cell injury. C57BL/6J wild-type mice were subjected to chronic alcohol feeding with or without rapamycin to inhibit mTORC1 activation. We revealed that palmitic acid (PA)-induced ER stress and suppression of LAMP2 and autophagy flux were mTORC1-dependent as rapamycin reversed such deleterious effects. C/EBP homologous protein (CHOP) was downstream of ATF4 which partially modulated LAMP2. Supplementation with rapamycin to alcohol-fed mice attenuated mTORC1 activation and ER stress, restored LAMP2 protein, and improved autophagy, leading to amelioration of alcohol-induced liver injury. Induction of mTORC1 signaling and CHOP were also detected in the liver of patients with severe alcoholic hepatitis. This study demonstrates that hepatic FFAs play a crucial role in the pathogenesis of ALD by activating mTORC1 signaling, thereby inducing ER stress and suppressing LAMP2-autophagy flux pathway, which represents an important mechanism of FFA-induced hepatocellular injury.
    Keywords:  ER stress; LAMP2; alcohol-related liver disease; free fatty acid; inflammation; mTORC1
  8. Front Oncol. 2021 ;11 727583
      Endoplasmic reticulum (ER) stress is a cellular process in response to stress stimuli in protecting functional activities. However, sustained hyperactive ER stress influences tumor growth and development. Hepatocytes are enriched with ER and highly susceptible to ER perturbations and stress, which contribute to immunosuppression and the development of aggressive and drug-resistant hepatocellular carcinoma (HCC). ER stress-induced inflammation and tumor-derived chemokines influence the immune cell composition at the tumor site. Consequently, a decrease in the CCL23 chemokine in hepatic tumors is associated with poor survival of HCC patients and could be a mechanism hepatic tumor cells use to evade the immune system. This article describes the prospective role of CCL23 in alleviating ER stress and its impact on the HCC tumor microenvironment in promoting antitumor immunity. Moreover, approaches to reactivate CCL23 combined with immune checkpoint blockade or chemotherapy drugs may provide novel opportunities to target hepatocellular carcinoma.
    Keywords:  antitumor immunity; chemokine ligand CCL23; endoplasmic reticulum; hepatocellular carcinoma; tumor microenvironment
  9. Front Immunol. 2021 ;12 705484
      Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapeutic procedure to treat hematological malignancies. However, the benefit of allo-HCT is limited by a major complication, chronic graft-versus-host disease (cGVHD). Since transmembrane and secretory proteins are generated and modified in the endoplasmic reticulum (ER), the ER stress response is of great importance to secretory cells including B cells. By using conditional knock-out (KO) of XBP-1, IRE-1α or both specifically on B cells, we demonstrated that the IRE-1α/XBP-1 pathway, one of the major ER stress response mediators, plays a critical role in B cell pathogenicity on the induction of cGVHD in murine models of allo-HCT. Endoribonuclease activity of IRE-1α activates XBP-1 signaling by converting unspliced XBP-1 (XBP-1u) mRNA into spliced XBP-1 (XBP-1s) mRNA but also cleaves other ER-associated mRNAs through regulated IRE-1α-dependent decay (RIDD). Further, ablation of XBP-1s production leads to unleashed activation of RIDD. Therefore, we hypothesized that RIDD plays an important role in B cells during cGVHD development. In this study, we found that the reduced pathogenicity of XBP-1 deficient B cells in cGVHD was reversed by RIDD restriction in IRE-1α kinase domain KO mice. Restraining RIDD activity per se in B cells resulted in an increased severity of cGVHD. Besides, inhibition of RIDD activity compromised B cell differentiation and led to dysregulated expression of MHC II and costimulatory molecules such as CD86, CD40, and ICOSL in B cells. Furthermore, restraining the RIDD activity without affecting XBP-1 splicing increased B cell ability to induce cGVHD after allo-HCT. These results suggest that RIDD is an important mediator for reducing cGVHD pathogenesis through targeting XBP-1s.
    Keywords:  ER stress; IRE-1α; RIDD; UPR; XBP-1; allo-HCT; chronic GVHD
  10. RSC Med Chem. 2021 Sep 23. 12(9): 1604-1611
      The endoplasmic reticulum (ER) is one of the crucial sub-cellular organelles controlling myriads of functions including protein biosynthesis, folding, misfolding and unfolding. As a result, dysregulation of these pathways in the ER is implicated in cancer development and progression. Subsequently, targeting the ER in cancer cells emerged as an interesting unorthodox strategy in next-generation anticancer therapy. However, development of small molecules to selectively target the ER for cancer therapy remained elusive and unexplored. To address this, herein, we have developed a novel small molecule library of sulfonylhydrazide-hydrazones through a short and concise chemical synthetic strategy. We identified a fluorescent small molecule that localized into the endoplasmic reticulum (ER) of HeLa cells, induced ER stress followed by triggering autophagy which was subsequently inhibited by chloroquine (autophagy inhibitor) to initiate apoptosis. This small molecule showed remarkable cancer cell killing efficacy in different cancer cells as mono and combination therapy with chloroquine, thus opening a new direction to illuminate ER-biology towards the development of novel anticancer therapeutics.