bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒09‒15
six papers selected by
Susan Logue
University of Manitoba


  1. Mol Metab. 2019 Sep;pii: S2212-8778(19)30573-3. [Epub ahead of print]27S S60-S68
    Ghosh R, Colon-Negron K, Papa FR.
      BACKGROUND: Myriad challenges to the proper folding and structural maturation of secretory pathway client proteins in the endoplasmic reticulum (ER) - a condition referred to as "ER stress" - activate intracellular signaling pathways termed the unfolded protein response (UPR).SCOPE OF REVIEW: Through executing transcriptional and translational programs the UPR restores homeostasis in those cells experiencing manageable levels of ER stress. But the UPR also actively triggers cell degeneration and apoptosis in those cells that are encountering ER stress levels that exceed irremediable thresholds. Thus, UPR outputs are "double-edged". In pancreatic islet β-cells, numerous genetic mutations affecting the balance between these opposing UPR functions cause diabetes mellitus in both rodents and humans, amply demonstrating the principle that the UPR is critical for the proper functioning and survival of the cell.
    MAJOR CONCLUSIONS: Specifically, we have found that the UPR master regulator IRE1α kinase/endoribonuclease (RNase) triggers apoptosis, β-cell degeneration, and diabetes, when ER stress reaches critical levels. Based on these mechanistic findings, we find that novel small molecule compounds that inhibit IRE1α during such "terminal" UPR signaling can spare ER stressed β-cells from death, perhaps affording future opportunities to test new drug candidates for disease modification in patients suffering from diabetes.
    Keywords:  Apoptosis; Diabetes mellitus; Endoplasmic reticulum stress; Endoribonuclease; Kinase; Small molecule kinase inhibitor; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.molmet.2019.06.012
  2. J R Soc Interface. 2019 Sep 27. 16(158): 20190288
    Stroberg W, Eilertsen J, Schnell S.
      The unfolded protein response (UPR) is a collection of cellular feedback mechanisms that seek to maintain protein folding homeostasis in the endoplasmic reticulum (ER). When the ER is 'stressed', through either high protein folding demand or undersupply of chaperones and foldases, stress sensing proteins in the ER membrane initiate the UPR. Recently, experiments have indicated that these signalling molecules detect stress by being both sequestered by free chaperones and activated by free unfolded proteins. However, it remains unclear what advantage this bidirectional sensor control offers stressed cells. Here, we show that combining positive regulation of sensor activity by unfolded proteins with negative regulation by chaperones allows the sensor to make a more informative measurement of ER stress. The increase in the information capacity of the combined sensing mechanism stems from stretching of the active range of the sensor, at the cost of increased uncertainty due to the integration of multiple signals. These results provide a possible rationale for the evolution of the observed stress-sensing mechanism.
    Keywords:  chemical sensing; endoplasmic reticulum stress; mutual information; signal integration; unfolded protein response
    DOI:  https://doi.org/10.1098/rsif.2019.0288
  3. Am J Cancer Res. 2019 ;9(8): 1766-1775
    Rajanala SH, Ringquist R, Cryns VL.
      Transformed cells are often selectively susceptible to depletion of the amino acid methionine, which induces growth arrest and/or apoptosis. In non-transformed cells, amino acid deficiency is sensed by two stress-activated kinases, general control nonderepressible 2 (GCN2) and protein kinase R-like endoplasmic reticulum kinase (PERK), which phosphorylate and inactivate elongation initiation factor 2 α (eIF2α), thereby suppressing global mRNA translation and inducing activated transcription factor (ATF4). ATF4 and its downstream transcriptional targets including Sestrin-2 constitute an adaptive integrated stress response. We postulated that methionine depletion activates the integrated stress response in breast cancer cells by a GCN2- and/or PERK-dependent mechanism and that selective disruption of one or both of these kinases would enhance the therapeutic activity of methionine restriction. Here we demonstrate that methionine restriction induces eIF2α phosphorylation and enhances ATF4 gene expression and protein levels of ATF4 and Sestrin-2 in triple (ER/PR/HER2)-negative breast cancer (TNBC) cells. However, knockdown of GCN2, PERK or both in TNBC cells did not prevent induction of ATF4 or Sestrin-2 by methionine restriction. In contrast, deletion of GCN2 in murine embryonic fibroblasts abrogated ATF4 and Sestrin-2 induction in response to methionine restriction. Moreover, knockdown of GCN2, PERK or both did not affect TNBC cell growth or apoptosis in response to methionine restriction. Overall, our findings point to a GCN2- and PERK-independent mechanism(s) by which methionine restriction activates the integrated stress response in TNBC cells. Elucidation of this pathway(s) could lead to strategies to enhance the therapeutic response of methionine restriction.
    Keywords:  Methionine restriction; cancer; integrated stress response; metabolism; nutrition
  4. Cell Death Dis. 2019 Sep 09. 10(9): 651
    Bastida-Ruiz D, Yart L, Wuillemin C, Ribaux P, Morris N, Epiney M, Martinez de Tejada B, Cohen M.
      The syncytiotrophoblast (STB) is a multinuclear layer forming the outer surface of the fetal part of the placenta deriving from villous cytotrophoblastic cell (vCTB) fusion and differentiation. This syncytialization process is characterized by morphological and biochemical alterations of the trophoblast, which probably require removal of pre-existing structures and proteins to maintain cell homeostasis and survival. Interestingly, autophagy, which allows degradation and recycling of cellular components, was shown to be activated in syncytiotrophoblast. Here we examined the involvement of endoplasmic reticulum stress (ERS) response in autophagy activation during vCTB syncytialization. We first demonstrated the activation of ERS response and autophagy during the time course of trophoblastic cell fusion and differentiation. Alteration of autophagy activation in vCTB by chemical treatments or Beclin-1 expression modulation leads to a decrease in trophoblastic syncytialization. Furthermore, ERS response inhibition by chemical treatment or siRNA strategy leads to a default in syncytialization, associated with alteration of autophagy markers and cell survival. From these data, we suggest that ERS response, by fine regulation of autophagy activation, may serve as an adaptive mechanism to promote cell survival during trophoblastic syncytialization.
    DOI:  https://doi.org/10.1038/s41419-019-1905-6
  5. Cell Death Dis. 2019 Sep 10. 10(9): 662
    Zhou L, Tan JH, Cao RC, Xu J, Chen XM, Qi ZC, Zhou SY, Li SB, Mo QX, Li ZW, Zhang GW.
      Chronic pancreatitis (CP) is a progressive, recurrent inflammatory disorder of the pancreas. Initiation and progression of CP can result from serine protease 1 (PRSS1) overaccumulation and the ensuing endoplasmic reticulum (ER) stress. However, how ER stress pathways regulate the development and progression of CP remains poorly understood. In the present study we aimed to elucidate the ER stress pathway involved in CP. We found high expression of the ER stress marker genes ATF6, XBP1, and CHOP in human clinical specimens. A humanized PRSS1 transgenic mouse was established and treated with caerulein to mimic the development of CP, as evidenced by pathogenic alterations, collagen deposition, and increased expression of the inflammatory factors IL-6, IL-1β, and TNF-α. ATF6, XBP1, and CHOP expression levels were also increased during CP development in this model. Acinar cell apoptosis was also significantly increased, accompanied by upregulated p53 expression. Inhibition of ATF6 or p53 suppressed the expression of inflammatory factors and progression of CP in the mouse model. Finally, we showed that p53 expression could be regulated by the ATF6/XBP1/CHOP axis to promote the development of CP. We therefore conclude that ATF6 signalling regulates CP progression by modulating pancreatic acinar cell apoptosis, which provides a target for ER stress-based diagnosis and treatment of CP.
    DOI:  https://doi.org/10.1038/s41419-019-1919-0
  6. Mol Metab. 2019 Sep;pii: S2212-8778(19)30566-6. [Epub ahead of print]27S S69-S80
    Sharma RB, Snyder JT, Alonso LC.
      BACKGROUND: A growing body of literature suggests the cell-intrinsic activity of Atf6α during ER stress responses has implications for tissue cell number during growth and development, as well as in adult biology and tumorigenesis [1]. This concept is important, linking the cellular processes of secretory protein synthesis and endoplasmic reticulum stress response with functional tissue capacity and organ size. However, the field contains conflicting observations, especially notable in secretory cell types like the pancreatic beta cell.SCOPE OF REVIEW: Here we summarize current knowledge of the basic biology of Atf6α, along with the pleiotropic roles Atf6α plays in cell life and death decisions and possible explanations for conflicting observations. We include studies investigating the roles of Atf6α in cell survival, death and proliferation using well-controlled methodology and specific validated outcome measures, with a focus on endocrine and metabolic tissues when information was available.
    MAJOR CONCLUSIONS: The net outcome of Atf6α on cell survival and cell death depends on cell type and growth conditions, the presence and degree of ER stress, and the duration and intensity of Atf6α activation. It is unquestioned that Atf6α activity influences the cell fate decision between survival and death, although opposite directions of this outcome are reported in different contexts. Atf6α can also trigger cell cycle activity to expand tissue cell number through proliferation. Much work remains to be done to clarify the many gaps in understanding in this important emerging field.
    Keywords:  Activating transcription factor 6; Apoptosis; Cell survival; Pancreatic beta cell; Replication
    DOI:  https://doi.org/10.1016/j.molmet.2019.06.005