bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒11‒03
nine papers selected by
Susan Logue
University of Manitoba


  1. Cancer Res. 2019 Oct 31. pii: canres.1116.2019. [Epub ahead of print]
    Moore PC, Qi JY, Thamsen M, Ghosh R, Peng J, Gliedt MJ, Meza-Acevedo R, Warren RE, Hiniker A, Kim GE, Maly DJ, Backes BJ, Papa FR, Oakes SA.
      Master regulators of the unfolded protein response (UPR) IRE1alpha and PERK promote adaptation or apoptosis depending on the level of endoplasmic reticulum (ER) stress. While the UPR is activated in many cancers, its effects on tumor growth remain unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNETs) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. Genetic and pharmacologic modulation of IRE1alpha and PERK in cultured cells, xenograft and spontaneous genetic (RIP-Tag2) mouse models of PanNETs revealed that UPR signaling was optimized for adaptation and that inhibiting either IRE1alpha or PERK led to hyperactivation and apoptotic signaling through the reciprocal arm, thereby halting tumor growth and survival. These results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers with elevated ER stress.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-1116
  2. J Biol Chem. 2019 10 30. pii: jbc.REV119.007036. [Epub ahead of print]
    Huang S, Xing Y, Liu Y.
      Inositol-requiring enzyme 1 (IRE1) is an endoplasmic reticulum (ER)-resident transmembrane protein that senses ER stress and is evolutionarily conserved from yeast to humans. IRE1 possesses both Ser/Thr protein kinase and endoribonuclease (RNase) activities within its cytoplasmic domain and is activated through autophosphorylation and dimerization/oligomerization. It mediates a critical arm of the unfolded protein response (UPR) to manage ER stress provoked by lumenal overload of unfolded/misfolded proteins. Emerging lines of evidence have revealed that in mammals, IRE1α functions as a multifunctional signal transducer that responds to metabolic cues and nutrient stress conditions, exerting profound and broad effects on metabolic homeostasis. In this review, we cover recent advances in our understanding of how IRE1α integrates a variety of metabolic and stress signals and highlight its tissue-specific or context-dependent metabolic activities. We also discuss how dysregulation of this metabolic stress sensor during handling of excessive nutrients in cells contributes to the progression of obesity and metabolic disorders.
    Keywords:  ER-associated degradation; Endoplasmic reticulum to nucleus signaling 1 (Ern1); IRE1α; Metabolic inflammation; Nutrient sensing; Regulated IRE1-depedendent decay (RIDD); X-box binding protein 1 (XBP1); endoplasmic reticulum stress (ER stress); signal transduction; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1074/jbc.REV119.007036
  3. Cells. 2019 Oct 29. pii: E1347. [Epub ahead of print]8(11):
    Sicari D, Igbaria A, Chevet E.
      : Discrimination between properly folded proteins and those that do not reach this state is necessary for cells to achieve functionality. Eukaryotic cells have evolved several mechanisms to ensure secretory protein quality control, which allows efficiency and fidelity in protein production. Among the actors involved in such process, both endoplasmic reticulum (ER) and the Golgi complex play prominent roles in protein synthesis, biogenesis and secretion. ER and Golgi functions ensure that only properly folded proteins are allowed to flow through the secretory pathway while improperly folded proteins have to be eliminated to not impinge on cellular functions. Thus, complex quality control and degradation machineries are crucial to prevent the toxic accumulation of improperly folded proteins. However, in some instances, improperly folded proteins can escape the quality control systems thereby contributing to several human diseases. Herein, we summarize how the early secretory pathways copes with the accumulation of improperly folded proteins, and how insufficient handling can cause the development of several human diseases. Finally, we detail the genetic and pharmacologic approaches that could be used as potential therapeutic tools to treat these diseases.
    Keywords:  EGAD; ER stress; ERAD; Golgi stress; protein quality control
    DOI:  https://doi.org/10.3390/cells8111347
  4. Mol Cell Endocrinol. 2019 Oct 24. pii: S0303-7207(19)30332-6. [Epub ahead of print] 110630
    Oikonomou C, Hendershot LM.
      Secreted, plasma membrane, and resident proteins of the secretory pathway are synthesized in the endoplasmic reticulum (ER) where they undergo post-translational modifications, oxidative folding, and subunit assembly in tightly monitored processes. An ER quality control (ERQC) system oversees protein maturation and ensures that only those reaching their native state will continue trafficking into the secretory pathway to reach their final destinations. Those that fail must be recognized and eliminated to maintain ER homeostasis. Two cellular mechanisms have been identified to rid the ER of terminally unfolded and aggregated proteins. ER-associated degradation (ERAD) was discovered nearly 30 years ago and entails the identification of improperly matured secretory pathway proteins and their retrotranslocation to the cytosol for degradation by the ubiquitin-proteasome system. ER-phagy has been more recently described and caters to larger, more complex proteins and protein aggregates that are not readily handled by ERAD. This pathway has unique upstream components and relies on the same downstream effectors of autophagy used in other cellular processes to deliver clients to lysosomes for degradation. In this review, we describe the main elements of ERQC, ERAD, and ER-phagy and focus on recent advances in these fields.
    Keywords:  ER chaperones; ER quality control; ER-Associated degradation; ER-Phagy; ERAD; ERQC; UPR; UPS; Ubiquitin proteasome system; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.mce.2019.110630
  5. J Biol Chem. 2019 Oct 29. pii: jbc.RA119.010450. [Epub ahead of print]
    Adams BM, Ke H, Gierasch LM, Gershenson A, Hebert DN.
      The protein quality-control machinery of the endoplasmic reticulum (ERQC) ensures that client proteins are properly folded. ERQC substrates may be recognized as non-native by the presence of exposed hydrophobic surfaces, free thiols, or processed N-glycans. How these features dictate which ERQC pathways engage a given substrate is poorly understood. Here, using metabolic labeling, immunoprecipitations, various biochemical assays and the human serpin antithrombin III (ATIII) as a model, we explored the role of ERQC systems in mammalian cells. Although ATIII has N-glycans and a hydrophobic core, we found that its quality control depended solely on free thiol content. Mutagenesis of all six Cys residues in ATIII to Ala resulted in its efficient secretion even though the product was not natively folded. ATIII variants with free thiols were retained in the ER but not degraded. These results provide insight into the hierarchy of ERQC systems and reveal a fundamental vulnerability of ERQC in a case of reliance on the thiol-dependent quality-control pathway.
    Keywords:  ER-mediated protein quality control (ERQC); N-linked glycosylation; UPR; disulfide; endoplasmic reticulum (ER); endoplasmic-reticulum-associated protein degradation (ERAD); protein folding; protein homeostasis; protein maturation; serpin; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1074/jbc.RA119.010450
  6. Elife. 2019 Nov 01. pii: e48434. [Epub ahead of print]8
    Morgens DW, Chan C, Kane AJ, Weir NR, Li A, Dubreuil MM, Tsui CK, Hess GT, Lavertu A, Han K, Polyakov N, Zhou J, Handy EL, Alabi P, Dombroski A, Yao D, Altman RB, Sello JK, Denic V, Bassik MC.
      The small molecule Retro-2 prevents ricin toxicity through a poorly-defined mechanism of action (MOA), which involves halting retrograde vesicle transport to the endoplasmic reticulum (ER). CRISPRi genetic interaction analysis revealed Retro-2 activity resembles disruption of the transmembrane domain recognition complex (TRC) pathway, which mediates post-translational ER-targeting and insertion of tail-anchored (TA) proteins, including SNAREs required for retrograde transport. Cell-based and in vitro assays show that Retro-2 blocks delivery of newly-synthesized TA-proteins to the ER-targeting factor ASNA1 (TRC40). An ASNA1 point mutant identified using CRISPR-mediated mutagenesis abolishes both the cytoprotective effect of Retro-2 against ricin and its inhibitory effect on ASNA1-mediated ER-targeting. Together, our work explains how Retro-2 prevents retrograde trafficking of toxins by inhibiting TA-protein targeting, describes a general CRISPR strategy for predicting the MOA of small molecules, and paves the way for drugging the TRC pathway to treat broad classes of viruses known to be inhibited by Retro-2.
    Keywords:  cell biology; genetics; genomics; human
    DOI:  https://doi.org/10.7554/eLife.48434
  7. Cell Death Differ. 2019 Oct 28.
    Hübner CA, Dikic I.
      Autophagy regulates the degradation of unnecessary or dysfunctional cellular components. This catabolic process requires the formation of a double-membrane vesicle, the autophagosome, that engulfs the cytosolic material and delivers it to the lysosome. Substrate specificity is achieved by autophagy receptors, which are characterized by the presence of at least one LC3-interaction region (LIR) or GABARAP-interaction motif (GIM). Only recently, several receptors that mediate the specific degradation of endoplasmic reticulum (ER) components via autophagy have been identified (the process known as ER-phagy or reticulophagy). Here, we give an update on the current knowledge about the role of ER-phagy receptors in health and disease.
    DOI:  https://doi.org/10.1038/s41418-019-0444-0
  8. Cells. 2019 Oct 30. pii: E1350. [Epub ahead of print]8(11):
    Machihara K, Namba T.
      Cancer cells modulate their metabolism to proliferate and survive under the metabolic stress condition, which is known as endoplasmic reticulum (ER) stress. Therefore, cancer cells should suppress ER stress-mediated cell death and induce autophagy-which recycles metabolites to provide energy and new macromolecules. In this study, we demonstrate that the ER membrane protein BAP31 acts to suppress adaptation to ER stress conditions, induce cell death, and suppress autophagy by forming a BAP31-STX17 protein complex. The loss of BAP31 stimulates tumor growth in metabolic stress conditions in vivo and enhances invasion activity. Therefore, BAP31 stimulates cell death and inhibits autophagy, and it can be considered a novel tumor suppressor factor that acts by preventing ER stress adaptation.
    Keywords:  BAP31; ER stress; STX17; autophagy; stress adaptation; tumor suppression
    DOI:  https://doi.org/10.3390/cells8111350
  9. J Cell Sci. 2019 Nov 01. pii: jcs238402. [Epub ahead of print]132(21):
    Himanen SV, Sistonen L.
      Cellular stress triggers reprogramming of transcription, which is required for the maintenance of homeostasis under adverse growth conditions. Stress-induced changes in transcription include induction of cyto-protective genes and repression of genes related to the regulation of the cell cycle, transcription and metabolism. Induction of transcription is mediated through the activation of stress-responsive transcription factors that facilitate the release of stalled RNA polymerase II and so allow for transcriptional elongation. Repression of transcription, in turn, involves components that retain RNA polymerase II in a paused state on gene promoters. Moreover, transcription during stress is regulated by a massive activation of enhancers and complex changes in chromatin organization. In this Review, we highlight the latest research regarding the molecular mechanisms of transcriptional reprogramming upon stress in the context of specific proteotoxic stress responses, including the heat-shock response, unfolded protein response, oxidative stress response and hypoxia response.
    Keywords:  Chromatin; Enhancer; Post-translational modification; Stress response; Transcription
    DOI:  https://doi.org/10.1242/jcs.238402