bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2022‒04‒17
six papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

  1. Eur J Immunol. 2022 Apr 13.
      The intracellular mechanisms safeguarding dendritic cell (DC) function are of biomedical interest in several immune-related diseases. Type 1 conventional DCs (cDC1s) are prominent targets of immunotherapy typified by constitutive activation of the unfolded protein response (UPR) sensor IRE1. Through its RNase domain, IRE1 regulates key processes in cDC1s including survival, endoplasmic reticulum architecture and function. However, most evidence linking IRE1 RNase with cDC1 biology emerges from mouse studies and it is currently unknown whether human cDC1s also activate the enzyme to preserve cellular homeostasis. In this work, we report that human cDC1s constitutively activate IRE1 RNase in steady-state, which is evidenced by marked expression of IRE1, XBP1s and target genes, and low levels of mRNA substrates of the IRE1 RNase domain. On a functional level, pharmacological inhibition of the IRE1 RNase domain curtailed IL-12 and TNF production by cDC1s upon stimulation with toll-like receptor agonists. Altogether, this work demonstrates that activation of the IRE1/XBP1s axis is a conserved feature of cDC1s across species and suggests that the UPR sensor may also play a relevant role in the biology of the human lineage. This article is protected by copyright. All rights reserved.
    Keywords:  DC activation; IRE1; UPR; XBP1s; cDC1s
  2. Front Mol Biosci. 2022 ;9 817392
      The endoplasmic reticulum, a vast reticular membranous network from the nuclear envelope to the plasma membrane responsible for the synthesis, maturation, and trafficking of a wide range of proteins, is considerably sensitive to changes in its luminal homeostasis. The loss of ER luminal homeostasis leads to abnormalities referred to as endoplasmic reticulum (ER) stress. Thus, the cell activates an adaptive response known as the unfolded protein response (UPR), a mechanism to stabilize ER homeostasis under severe environmental conditions. ER stress has recently been postulated as a disease research breakthrough due to its significant role in multiple vital cellular functions. This has caused numerous reports that ER stress-induced cell dysfunction has been implicated as an essential contributor to the occurrence and development of many diseases, resulting in them targeting the relief of ER stress. This review aims to outline the multiple molecular mechanisms of ER stress that can elucidate ER as an expansive, membrane-enclosed organelle playing a crucial role in numerous cellular functions with evident changes of several cells encountering ER stress. Alongside, we mainly focused on the therapeutic potential of ER stress inhibition in gastrointestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer. To conclude, we reviewed advanced research and highlighted future treatment strategies of ER stress-associated conditions.
    Keywords:  cell death; colon cancer; endoplasmic reticulum stress; inflammatory bowel disease; treatment target; unfolded protein response
  3. Hepatology. 2022 Apr 10.
      BACKGROUND AND AIMS: Cholesterol ester biosynthesis and homeostasis play critical roles in many cancers including hepatocellular carcinoma (HCC), but their exact mechanistic contributions to HCC disease development are unknown.APPROACH AND RESULTS: Here, we report a newly found role of tumor suppressor P53 in its repressing ubiquitin specific peptidase 19 (USP19) and sterol O-acyltransferase 1 (SOAT1), which maintains the cholesterol ester homeostasis. USP19 enhances cholesterol esterification and contributes to hepatocarcinogenesis by deubiquitinating and stabilizing SOAT1. Loss of either SOAT1 or USP19 dramatically attenuates cholesterol esterification and hepatocarcinogenesis in the p53-deficient mice fed with either normal chow diet (NCD) or high-cholesterol, high-fat diet (HCHFD). SOAT1 inhibitor avasimibe has more inhibitory effect on HCC progression in HCHFD-maintained p53-deficient mice when compared to the inhibitors of de novo cholesterol synthesis. Consistent with our findings in mouse model, the P53-USP19-SOAT1 signaling axis is also dysregulated in human HCCs.
    CONCLUSIONS: Collectively, our findings demonstrate that SOAT1 participates in hepatocarcinogenesis by increasing cholesterol esterification, thus indicating that SOAT1 is a potential biomarker and therapeutic target in P53-deficient HCC.
  4. Biochem Biophys Res Commun. 2022 Apr 06. pii: S0006-291X(22)00522-8. [Epub ahead of print]609 62-68
      RNF213, a susceptibility gene for moyamoya disease, is associated with stress responses to various stressors. We previously reported that Rnf213 knockout (KO) mitigated endoplasmic reticulum (ER) stress-induced diabetes in the Akita mouse model of diabetes. However, the role of RNF213 in ER stress regulation remains unknown. In the present study, RNF213 knockdown significantly inhibited the upregulation of ER stress markers (CHOP and spliced XBP1) by chemical ER stress-inducers in HeLa cells. Levels of SEL1L, a critical molecule in ER-associated degradation (ERAD), were increased by RNF213 knockdown, and SEL1L knockdown prevented the inhibitory effect of RNF213 suppression on ER stress in HeLa cells, indicating SEL1L involvement in this inhibition of ER stress. SEL1L upregulation was also confirmed in pancreatic islets of Rnf213 KO/Akita mice and in Rnf213 KO mouse embryonic fibroblasts. Additionally, RNF213 suppression increased levels of HRD1, which forms a complex with SEL1L to degrade misfolded protein in cells under ER stress. In conclusion, we demonstrate that RNF213 depletion inhibits ER stress possibly through elevation of the SEL1L-HRD1 complex, thereby promoting ERAD in vitro and in vivo.
    Keywords:  Endoplasmic reticulum stress; HRD1; Moyamoya disease; RNF213; SEL1L
  5. Nan Fang Yi Ke Da Xue Xue Bao. 2022 Mar 20. 42(3): 432-437
      OBJECTIVE: To explore the mechanism by which estradiol modulates the immunophenotype of macrophages through the endoplasmic reticulum stress pathway.METHODS: Peritoneal macrophages isolated from C57 mice were cultured in the presence of 60 ng/mL interferon-γ (IFN-γ) followed by treatment with estradiol (1.0 nmol/L) alone, estradiol with estrogen receptor antagonist (Acolbifene, 4 nmol/L), estradiol with IRE1α inhibitor (4 μ 8 C), or estradiol with IRE1α agonist. After the treatments, the expression levels of MHC-Ⅱ, iNOS and endoplasmic reticulum stress marker proteins IRE1α, eIF2α and ATF6 in the macrophages were detected with Western blotting, and the mRNA levels of TGF-β, IL-6, IL-10 and TNF-α were detected with RT-PCR.
    RESULTS: Estrogen treatment of the macrophages significantly decreased the expressions of M1-related proteins MHC-Ⅱ (P=0.021) and iNOS (P < 0.001) and the mRNA expressions of TNF-α (P=0.003) and IL-6 (P=0.004), increased the mRNA expression of TGF-β (P=0.002) and IL-10 (P=0.008), and up-regulated the protein expressions of IRE1α (P < 0.001) and its downstream transcription factor XBP-1 (P < 0.001). Addition of the estrogen inhibitor obviously blocked the effect of estrogen. Compared with estrogen treatment alone, combined treatment of the macrophages with estrogen and the IRE1α inhibitor 4 μ 8 C significantly up-regulated the protein expressions of MHC-Ⅱ (P=0.002) and iNOS (P=0.003) and the mRNA expressions of TNF-α (P=0.003) and IL-6 (P=0.024), and obviously down-regulated the mRNA expression of TGF-β (P < 0.001) and IL-10 (P < 0.001); these changes were not observed in cells treated with estrogen and the IRE1α agonist.
    CONCLUSION: Estrogen can inhibit the differentiation of murine macrophages into a pro-inflammatory phenotype by up-regulating the IRE1α-XBP-1 signaling axis, thereby producing an inhibitory effect on inflammatory response.
    Keywords:  endoplasmic reticulum stress pathway; estrogen; macrophages
  6. Blood Cancer Discov. 2022 Apr 11. pii: bloodcandisc.BCD-21-0144-E.2021. [Epub ahead of print]
      Approximately 20% of patients with myeloproliferative neoplasms (MPNs) harbor mutations in the gene calreticulin (CALR), with 80% of those mutations classified as either type 1 or type 2. While type 2 CALR mutant proteins retain many of the Ca2+ binding sites present in the wild type protein, type 1 CALR mutant proteins lose these residues. The functional consequences of this differential loss of Ca2+ binding sites remain yet unexplored. Here, we show that the loss of Ca2+ binding residues in the type 1 mutant CALR protein directly impairs its Ca2+ binding ability, which in turn leads to depleted endoplasmic reticulum (ER) Ca2+ and subsequent activation of the IRE1a/XBP1 pathway of the unfolded protein response. Genetic or pharmacological inhibition of IRE1a/XBP1 signaling induces cell death only in type 1 mutant but not type 2 mutant or wild type CALR-expressing cells, and abrogates type 1 mutant CALR-driven MPN disease progression in vivo.