bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2022‒04‒24
nine papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

  1. Mol Cell. 2022 Apr 21. pii: S1097-2765(22)00263-5. [Epub ahead of print]82(8): 1477-1491
      Endoplasmic reticulum quality control (ERQC) pathways comprising chaperones, folding enzymes, and degradation factors ensure the fidelity of ER protein folding and trafficking to downstream secretory environments. However, multiple factors, including tissue-specific secretory proteomes, environmental and genetic insults, and organismal aging, challenge ERQC. Thus, a key question is: how do cells adapt ERQC to match the diverse, ever-changing demands encountered during normal physiology and in disease? The answer lies in the unfolded protein response (UPR), a signaling mechanism activated by ER stress. In mammals, the UPR comprises three signaling pathways regulated downstream of the ER membrane proteins IRE1, ATF6, and PERK. Upon activation, these UPR pathways remodel ERQC to alleviate cellular stress and restore ER function. Here, we describe how UPR signaling pathways adapt ERQC, highlighting their importance for maintaining ER function across tissues and the potential for targeting the UPR to mitigate pathologies associated with protein misfolding diseases.
    Keywords:  ATF6; ER-associated degradation; ERAD; IRE1; PERK; XBP1s; amyloid; chaperone; loss-of-function disease; protein aggregation; protein misfolding disease
  2. Pharmaceuticals (Basel). 2022 Mar 25. pii: 401. [Epub ahead of print]15(4):
      A growing body of scientific evidence indicates that protein homeostasis, also designated as proteostasis, is causatively linked to chronic diabetic nephropathy (DN). Experimental studies have demonstrated that the insulin signaling in podocytes maintain the homeostatic unfolded protein response (UPR). Insulin signaling via the insulin receptor non-canonically activates the spliced X-box binding protein-1 (sXBP1), a highly conserved endoplasmic reticulum (ER) transcription factor, which regulates the expression of genes that control proteostasis. Defective insulin signaling in mouse models of diabetes or the genetic disruption of the insulin signaling pathway in podocytes propagates hyperglycemia induced maladaptive UPR and DN. Insulin resistance in podocytes specifically promotes activating transcription factor 6 (ATF6) dependent pathogenic UPR. Akin to insulin, recent studies have identified that the cytoprotective effect of anticoagulant serine protease-activated protein C (aPC) in DN is mediated by sXBP1. In mouse models of DN, treatment with chemical chaperones that improve protein folding provides an additional benefit on top of currently used ACE inhibitors. Understanding the molecular mechanisms that transmute renal cell specific adaptive responses and that deteriorate renal function in diabetes will enable researchers to develop new therapeutic regimens for DN. Within this review, we focus on the current understanding of homeostatic mechanisms by which UPR is regulated in DN.
    Keywords:  ATF6; ER stress; XBP1; aPC; diabetic nephropathy; insulin signaling; podocytes; unfolded protein response
  3. J Cell Biol. 2022 Jun 06. pii: e202111068. [Epub ahead of print]221(6):
      Dendritic cells (DCs) promote adaptive immunity by cross-presenting antigen-based epitopes to CD8+ T cells. DCs process internalized protein antigens into peptides that enter the endoplasmic reticulum (ER), bind to major histocompatibility type I (MHC-I) protein complexes, and are transported to the cell surface for cross-presentation. DCs can exhibit activation of the ER stress sensor IRE1α without ER stress, but the underlying mechanism remains obscure. Here, we show that antigen-derived hydrophobic peptides can directly engage ER-resident IRE1α, masquerading as unfolded proteins. IRE1α activation depletes MHC-I heavy-chain mRNAs through regulated IRE1α-dependent decay (RIDD), curtailing antigen cross-presentation. In tumor-bearing mice, IRE1α disruption increased MHC-I expression on tumor-infiltrating DCs and enhanced recruitment and activation of CD8+ T cells. Moreover, IRE1α inhibition synergized with anti-PD-L1 antibody treatment to cause tumor regression. Our findings identify an unexpected cell-biological mechanism of antigen-driven IRE1α activation in DCs, revealing translational potential for cancer immunotherapy.
  4. Life Sci. 2022 Apr 19. pii: S0024-3205(22)00254-5. [Epub ahead of print] 120554
      Nowadays, the nutraceutical agent sulforaphane (SFN) shows great versatility in turning on different cellular responses. Mainly, this isothiocyanate acts as a master regulator of cellular homeostasis due to its antioxidant response and cytoplasmic, mitochondrial, and endoplasmic reticulum (ER) protein modulation. Even more, SFN acts as an effective strategy to counteract oxidative stress, apoptosis, and ER stress, among others as seen in different injury models. Particularly, ER stress is buffered by the unfolded protein response (UPR) activation, which is the first instance in orchestrating the recovery of ER function. Interestingly, different studies highlight a close interrelationship between ER stress and oxidative stress, two events driven by the accumulation of reactive oxygen species (ROS). This response inevitably perpetuates itself and acts as a vicious cycle that triggers the development of different pathologies, such as cardiovascular diseases, neurodegenerative diseases, and others. Accordingly, it is vital to target ER stress and oxidative stress to increase the effectiveness of clinical therapies used to treat these diseases. Therefore, our study is focused on the role of SFN in preserving cellular homeostasis balance by regulating the ER stress response through the Nrf2-modulated antioxidant pathway.
    Keywords:  1,2-dithio-3-thione; 6-hydroxydopamine; Dithiothreitol; Endoplasmic reticulum stress; Hydrogen peroxide; Nrf2; Oxidative stress; Reactive oxygen species; Sulforaphane; Thapsigargin; Tunycamicin
  5. Eur J Pharmacol. 2022 Apr 14. pii: S0014-2999(22)00218-7. [Epub ahead of print]924 174957
      DNA damage response (DDR) comprising DNA repair and cell-cycle checkpoint pathways, is considered as a protective process that maintains the integrity of the genome. However, this mechanism may not be favorable in the context of cancer. Indeed, studies have shown that DDR and repair mechanisms can be involved in the development of different cancers. Furthermore, they may lead to the failure of therapeutic approaches. Thus, studying these mechanisms can be beneficial in a better understanding of cancer development and developing more efficient treatments. Scopus, Google Scholar, and PubMed databases were used for searching articles published on "DNA damage response and DNA repair in the development and treatment of brain tumors". Herein, we review the literature on DNA damage response and DNA repair mechanisms in the development of brain tumors, such as glioma, glioblastoma, and medulloblastoma. Moreover, we summarize the studies that conducted on the role of targeting components of DNA damage response and DNA repair in treating different types of brain cancers, enhancing the currently available therapeutic approaches, and solving the problems in the field of brain cancer therapy.
    Keywords:  DNA damage response; Drug resistance; Glioblastoma; Glioma; Medulloblastoma
  6. Biochem Biophys Res Commun. 2022 Apr 11. pii: S0006-291X(22)00564-2. [Epub ahead of print]610 70-76
      Bone cells of various lineages become senescent in bone microenvironment. Senotherapies that clear the senescent bone cells improve bone microarchitecture of aged bones. However, the mechanisms underlie for the formation and maintenance of senescent bone cells are largely unknown. Here, we focus on the relationship between endoplasmic reticulum stress (ER stress)-activated unfolded protein response (UPR) signaling and cellular senescence of bone marrow mesenchymal stem cells (BMSCs). The PKR-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2 α(eIF2α) signaling branch was specifically activated and tightly regulated in senescent BMSCs induced by hydrogen peroxide (H2O2). However, blocking PERK-eIF2α signaling with AMG'44 could not reverse the cellular senescence phenotype of senescent BMSCs. Treated the senescent cells with salubrinal, an inhibitor for dephosphorylation of eIF2α, decreased SA-β-Gal positive cells and the expression of markers for cellular senescence. Moreover, salubrinal enhanced the apoptosis of senescent BMSCs and upregulated expression of Chop and BIM. Furthermore, salubrinal treatment significantly improved the osteogenesis capacity of senescent BMSCs as reflected by the increase of Alp, Runx2 and Osteocalcin, the formation of Alp-positive staining cells and matrix mineralization. Salubrinal administration results in significant recovery in the bone microarchitecture of senile SAMP6 mice. Taken together, our data reveal an undefined role of PERK-eIF2α signaling in the maintenance of cellular senescent phenotype in BMSCs. The activation of eIF2α signaling with salubrinal is helpful for the clearance of senescent BMSCs and the improvement of bone integrity of aged mice.
    Keywords:  Bone marrow stromal cells; Cellular senescence; ER stress; Salubrinal; Senolytics
  7. Infect Immun. 2022 Apr 18. e0007922
      Chlamydia psittaci is an important pathogen that causes chronic and atypical pneumonia in humans. Autophagy and the unfolded protein response (UPR) are important mechanisms for regulating the growth of infectious parasitic pathogens in living cells. Here, we explored whether C. psittaci infection induced autophagy via the UPR and the effect of these cellular responses on the survival and replication of C. psittaci in human bronchial epithelial cells (HBEs). Not only were the numbers of autophagosomes and the expression of LC3-II and Beclin1 increased following C. psittaci infection of HBEs, but also the expression of p62 (also called sequestosome-1) was downregulated. Moreover, after C. psittaci infection, the UPR and UPR sensors PERK/eIF2α and IRE1α/XBP1 were activated, but not the ATF6 pathway. When either Bip siRNA was used to block normal initiation of the UPR, or activation of the PERK and IER1α pathways was blocked with specific inhibitors GSK2606414 and 4μ8C, the level of autophagy caused by C. psittaci infection was significantly inhibited. Furthermore, blocking activation of the UPR and associated pathways significantly reduced the number of C. psittaci inclusions. Our research suggests that the UPR, via the PERK and IRE1α, but not ATF6 signaling pathways, regulates HBE-cell autophagy induced by C. psittaci infection and the replication of C. psittaci.
    Keywords:  ATF6; Chlamydia psittaci; IRE1α; PERK; autophagy; unfolded protein reaction
  8. Nutrients. 2022 Apr 18. pii: 1680. [Epub ahead of print]14(8):
      Gamma-aminobutyric acid (GABA) is a natural amino acid with antioxidant activity and is often considered to have therapeutic potential against obesity. Obesity has long been linked to ROS and ER stress, but the effect of GABA on the ROS-associated ER stress axis has not been thoroughly explored. Thus, in this study, the effect of GABA and fermented Curcuma longa L. extract enriched with GABA (FCLL-GABA) on the ROS-related ER stress axis and inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) sulfonation were examined with the HFD model to determine the underlying anti-obesity mechanism. Here, GABA and FCLL-GABA supplementations significantly inhibited the weight gain in HFD fed mice. The GABA and FCLL-GABA supplementation lowered the expressions of adipogenic transcription factors such as PPAR-γ, C/EBPα, FAS, and SREBP-1c in white adipose tissue (WAT) and liver from HFD-fed mice. The enhanced hyper-nutrient dysmetabolism-based NADPH oxidase (Nox) 4 and the resultant IRE1α sulfonation-RIDD-SIRT1 decay under HFD conditions were controlled with GABA and FCLL-GABA. Notably, GABA and FCLL-GABA administration significantly increased AMPK and sirtuin 1 (SIRT1) levels in WAT of HFD-fed mice. These significant observations indicate that ER-localized Nox4-induced IRE1α sulfonation results in the decay of SIRT1 as a novel mechanism behind the positive implications of GABA on obesity. Moreover, the investigation lays a firm foundation for the development of FCLL-GABA as a functional ingredient.
    Keywords:  IRE1α; NADPH oxidase; SIRT1; decay; obesity
  9. Nucleic Acids Res. 2022 Apr 19. pii: gkac242. [Epub ahead of print]
      Small molecule targeting of self-splicing RNAs like group I and II introns has been limited in part by the lack of a universal high-throughput screening platform for studies of splicing inhibition and kinetics. Here, we present the development of a molecular beacon assay for monitoring the accumulation of spliced exons during RNA splicing reactions. In this case, we applied it to the autocatalyzed reaction of the H.c.LSU group II intron found in the mitochondria of the pathogenic dimorphic fungus Histoplasma capsulatum. We find that a molecular beacon with the loop length of 18 nucleotides selectively recognizes ligated exons formed during self-splicing and exhibits high fluorescent signal upon binding of its target. We demonstrate that the fluorescent assay using molecular beacons can be successfully applied to kinetic characterization of the splicing reaction and determination of inhibition constants for small molecules. The results presented herein offer support for a molecular beacon approach to identifying small molecule inhibitors of intron splicing.