bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021‒08‒01
seven papers selected by
Susan Logue
University of Manitoba

  1. Sci Transl Med. 2021 Jul 28. pii: eaba9796. [Epub ahead of print]13(604):
      Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia, and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic β cells is enhanced, which can lead to proinsulin misfolding that aggravates endoplasmic reticulum (ER) protein homeostasis in β cells. Moreover, increased circulating insulin may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in β cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germline Chop gene deletion preserved β cells in high-fat diet (HFD)-fed mice and in leptin receptor-deficient db/db mice. In the current study, we further investigated whether targeting Chop/Ddit3 specifically in murine β cells conferred therapeutic benefits. First, we showed that Chop deletion in β cells alleviated β cell ER stress and delayed glucose-stimulated insulin secretion (GSIS) in HFD-fed mice. Second, β cell-specific Chop deletion prevented liver steatosis and hepatomegaly in aged HFD-fed mice without affecting basal glucose homeostasis. Third, we provide mechanistic evidence that Chop depletion reduces ER Ca2+ buffering capacity and modulates glucose-induced islet Ca2+ oscillations, leading to transcriptional changes of ER chaperone profile ("ER remodeling"). Last, we demonstrated that a GLP1-conjugated Chop antisense oligonucleotide strategy recapitulated the reduction in liver triglycerides and pancreatic insulin content. In summary, our results demonstrate that Chop depletion in β cells provides a therapeutic strategy to alleviate dysregulated insulin secretion and consequent fatty liver disease in T2D.
  2. FEBS J. 2021 Jul 31.
      Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It currently ranks as one of the most aggressive and deadly cancers worldwide, with an increasing mortality rate and limited treatment options. An important hallmark of liver pathologies, such as liver fibrosis and HCC, is the accumulation of misfolded and unfolded proteins in the lumen of the endoplasmic reticulum (ER), which induces ER-stress and leads to the activation of the unfolded protein response (UPR). Upon accumulation of misfolded proteins, ER-stress is sensed through three transmembrane proteins, IRE1α, PERK and ATF6, which trigger the UPR to either alleviate ER-stress or induce apoptosis. Increased expression of ER-stress markers has been widely shown to correlate with fibrosis, inflammation, drug resistance and overall HCC aggressiveness, as well as poor patient prognosis. While preclinical in vivo cancer models and in vitro approaches have shown promising results by pharmacologically targeting ER-stress mediators, the major challenge of this therapeutic strategy lies in specifically and effectively targeting ER-stress in HCC. Furthermore, both ER-stress inducers and inhibitors have been shown to ameliorate HCC progression, adding to the complexity of targeting ER-stress players as an anti-cancer strategy. More studies are needed to better understand the dual role and molecular background of ER-stress in HCC, as well as its therapeutic potential for patients with liver cancer.
    Keywords:  ER-stress; fibrosis; hepatocellular carcinoma; tumor microenvironment; unfolded protein response
  3. Front Cell Dev Biol. 2021 ;9 671461
      Defects in stress responses are important contributors in many chronic conditions including cancer, cardiovascular disease, diabetes, and obesity-driven pathologies like non-alcoholic steatohepatitis (NASH). Specifically, endoplasmic reticulum (ER) stress is linked with these pathologies and control of ER stress can ameliorate tissue damage. MicroRNAs have a critical role in regulating diverse stress responses including ER stress. Here, we show that miR-494 plays a functional role during ER stress. Pharmacological ER stress inducers (tunicamycin (TCN) and thapsigargin) and hyperglycemia robustly increase the expression of miR-494 in vitro. ATF6 impacts the primary miR-494 levels whereas all three ER stress pathways are necessary for the increase in mature miR-494. Surprisingly, miR-494 pretreatment dampens the induction and magnitude of ER stress in response to TCN in endothelial cells and increases cell viability. Conversely, inhibition of miR-494 increases ER stress de novo and amplifies the effects of ER stress inducers. Using Mass Spectrometry (TMT-MS) we identified 23 proteins that are downregulated by both TCN and miR-494 in cultured human umbilical vein endothelial cells. Among these, we found 6 transcripts which harbor a putative miR-494 binding site. We validated the anti-apoptotic gene BIRC5 (survivin) and GINS4 as targets of miR-494 during ER stress. In summary, our data indicates that ER stress driven miR-494 may act in a feedback inhibitory loop to dampen downstream ER stress signaling.
    Keywords:  ER stress; UPR – unfolded protein response; cell stress adaptation; endothelial cells; microRNA
  4. Front Cell Dev Biol. 2021 ;9 684526
      The endoplasmic reticulum (ER) is one of the most important cellular organelles and is essential for cell homeostasis. Upon external stimulation, ER stress induces the unfolded protein response (UPR) and ER-associated degradation (ERAD) to maintain ER homeostasis. However, persistent ER stress can lead to cell damage. ER-phagy is a selective form of autophagy that ensures the timely removal of damaged ER, thereby protecting cells from damage caused by excessive ER stress. As ER-phagy is a newly identified form of autophagy, many receptor-mediated ER-phagy pathways have been discovered in recent years. In this review, we summarize our understanding of the maintenance of ER homeostasis and describe the receptors identified to date. Finally, the relationships between ER-phagy and diseases are also discussed.
    Keywords:  ER-phagy; ERAD; autophagy; endoplasmic reticulum (ER); unfolded protein response (UPR)
  5. FEBS Open Bio. 2021 Jul 28.
      Endoplasmic reticulum (ER) stress is a cellular stress condition involving disturbance in the folding capacity of the ER caused by endogenous and exogenous factors. ER stress signaling pathways affect tumor malignant growth, angiogenesis and progression, and promote the anti-tumor effects of certain drugs. However, the impact of ER stress on the vasculogenic mimicry (VM) phenotype of cancer cells has not been well addressed. VM is a phenotype which mimics vasculogenesis by forming patterned tubular networks, which are related to stemness and aggressive behaviors of cancer cells. In this study we employed tunicamycin (TM), a UPR-activating agent, to induce ER stress in aggressive triple negative MDA-MB-231 breast cancer cells, which exhibit a VM phenotype in 3D Matrigel cultures. TM-induced ER stress was able to inhibit the VM phenotype. In addition to the tumorspheroid phenotype observed upon inhibiting the VM phenotype, we observed alterations in glycosylation of integrin β1, loss of VE-cadherin and a decrease in stem cell marker Bmi-1. Further study revealed decreased activated TGF-β1, Smad2/3, Phospho-Smad2 and β-catenin. β-catenin knockdown markedly inhibited the VM phenotype and resulted in the loss of VE-cadherin. The data suggest that the activation of ER stress inhibited VM phenotype formation of breast cancer cells via both the TGF-β1/Smad2/3 and β-catenin signaling pathways. The discovery of prospective regulatory mechanisms involved in ER stress and VM in breast cancer could lead to more precisely targeted therapies that inhibit vessel formation and affect tumor progression.
    Keywords:  Endoplasmic reticulum stress; TGF-β1; breast cancer; vasculogenic mimicry; β-catenin
  6. Front Physiol. 2021 ;12 707634
      Diabetic cardiomyopathy has been associated with mitochondrial damage. Mitochondria-endoplasmic reticulum (ER) contact is an important determinant of mitochondrial function and ER homeostasis. We therefore investigated whether hyperglycemia can damage the mitochondria by increasing their contact with the ER in cardiomyocytes. We found that hyperglycemia induced mitochondria-ER contact in cardiomyocytes, as evidenced by the increased MMM1, MDM34, and BAP31 expressions. Interestingly, the silencing of Mfn2 reduced the cooperation between the mitochondria and the ER in cardiomyocytes. Mfn2 silencing improved cardiomyocyte viability and function under hyperglycemic conditions. Additionally, the silencing of Mfn2 markedly attenuated the release of calcium from the ER to the mitochondria, thereby preserving mitochondrial metabolism in cardiomyocytes under hyperglycemic conditions. Mfn2 silencing reduced mitochondrial reactive oxygen species production, which reduced mitochondria-dependent apoptosis in hyperglycemia-treated cardiomyocytes. Finally, Mfn2 silencing attenuated ER stress in cardiomyocytes subjected to high-glucose stress. These results demonstrate that Mfn2 promotes mitochondria-ER contact in hyperglycemia-treated cardiomyocytes. The silencing of Mfn2 sustained mitochondrial function, suppressed mitochondrial calcium overload, prevented mitochondrial apoptosis, and reduced ER stress, thereby enhancing cardiomyocyte survival under hyperglycemic conditions.
    Keywords:  ER; Mfn2; apoptosis; mitochondria; mitochondria-ER contact
  7. J Clin Invest. 2021 Jul 29. pii: 147836. [Epub ahead of print]
      Ischemic cardiomyopathy is associated with an increased risk of sudden death, activation of the unfolded protein response (UPR), and reductions in multiple cardiac ion channels. When activated, the protein kinase-like ER kinase (PERK) branch of the UPR reduces protein translation and abundance. We hypothesized that PERK inhibition could prevent ion channel downregulation and reduce arrhythmic risk after myocardial infarct (MI). MI induced by coronary artery ligation resulted in mice exhibited reduced ion channel levels, ventricular tachycardia (VT), and prolonged corrected intervals between the Q and T waves of the ECGs (QTc). Protein levels of major cardiac ion channels were decreased. MI cardiomyocytes showed significantly prolonged action potential duration and decreased maximum upstroke velocity. Cardiac-specific PERK knockout (PERKKO) reduced electrical remodeling in response to MI with shortened QTc intervals, less VT episodes, and higher survival rates (P<0.05 vs. MI). Pharmacological PERK inhibition had similar effects. In conclusion, activated PERK during MI contributed to arrhythmic risk by downregulation of select cardiac ion channels. PERK inhibition prevented these changes and reduced arrhythmic risk. These results suggest that ion channel downregulation during MI is a fundamental arrhythmic mechanism and maintaining ion channel levels is antiarrhythmic.
    Keywords:  Arrhythmias; Cardiology; Cell stress; Ion channels