bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒08‒25
five papers selected by
Susan Logue
University of Manitoba

  1. Front Immunol. 2019 ;10 1789
    Lara-Reyna S, Scambler T, Holbrook J, Wong C, Jarosz-Griffiths HH, Martinon F, Savic S, Peckham D, McDermott MF.
      Cystic Fibrosis (CF) is a recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR mutations cause dysregulation of channel function with intracellular accumulation of misfolded proteins and endoplasmic reticulum (ER) stress, with activation of the IRE1α-XBP1 pathway that regulates a subset of unfolded protein response (UPR) genes. This pathway regulates a group of genes that control proinflammatory and metabolic responses in different immune cells; however, the metabolic state of immune cells and the role of this pathway in CF remain elusive. Our results indicate that only innate immune cells from CF patients present increased levels of ER stress, mainly affecting neutrophils, monocytes, and macrophages. An overactive IRE1α-XBP1 pathway reprograms CF M1 macrophages toward an increased metabolic state, with increased glycolytic rates and mitochondrial function, associated with exaggerated production of TNF and IL-6. This hyper-metabolic state, seen in CF macrophages, is reversed by inhibiting the RNase domain of IRE1α, thereby decreasing the increased glycolic rates, mitochondrial function and inflammation. Altogether, our results indicate that innate immune cells from CF patients are primarily affected by ER stress. Moreover, the IRE1α-XBP1 pathway of the UPR is responsible for the hyper-metabolic state seen in CF macrophages, which is associated with the exaggerated inflammatory response. Modulating ER stress, metabolism and inflammation, by targeting IRE1α, may improve the metabolic fitness of macrophages, and other immune cells in CF and other immune-related disorders.
    Keywords:  IRE1; UPR; XBP1; cystic fibrosis; inflammation; macrophages; metabolism
  2. J Neurochem. 2019 Aug 23.
    van Ziel AM, Wolzak K, Nölle A, Hoetjes PJ, Berenjeno-Correa E, van Anken E, Struys EA, Scheper W.
      The unfolded protein response (UPR) is one of the major cell-autonomous proteostatic stress responses. The UPR has been implicated in the pathogenesis of neurodegenerative diseases and is therefore actively investigated as therapeutic target. In this respect, cell non-autonomous effects of the UPR including the reported cell-to-cell transmission of UPR activity may be highly important. A pharmaca-based UPR induction was employed to generate conditioned media (CM) from CM-donating neuronal ("donor") cells (SK-N-SH and primary mouse neurons). As previously reported, upon subsequent transfer of CM to naive neuronal "acceptor" cells, we confirmed UPR target mRNA and protein expression by qPCR and automated microscopy. However, UPR target gene expression was also induced in the absence of donor cells, indicating carry-over of pharmaca. Genetic induction of single pathways of the UPR in donor cells did not result in UPR transmission to acceptor cells. Moreover, no transmission was detected upon full UPR activation by nutrient deprivation or inducible expression of the heavy chain of immunoglobulin M (IgM) in donor ​HeLa cells. In addition, in direct co-culture of donor cells expressing the IgM heavy chain and fluorescent UPR reporter acceptor ​HeLa cells, UPR transmission was not observed. In conclusion, carry-over of pharmaca is a major confounding factor in pharmaca-based UPR transmission protocols that are therefore unsuitable to study cell-to-cell UPR transmission. In addition, the absence of UPR transmission in non-pharmaca-based models of UPR activation indicates that cell-to-cell UPR transmission does not occur in cell culture.
    Keywords:  UPR transmission; Unfolded protein response; cell non-autonomous; endoplasmic reticulum stress; neurodegenerative diseases; proteostasis
  3. Cell Calcium. 2019 Aug 08. pii: S0143-4160(19)30123-X. [Epub ahead of print]83 102056
    Agellon LB, Michalak M.
      IRE1α is well known as a regulator of one branch of the UPR pathway that is activated during ER stress that operates to regain ER proteostasis. In a recent paper, Carreras-Sureda et al. show that IRE1α is also a structural component of MAMs and facilitates the uptake of Ca2+ by mitochondria.
    Keywords:  Calcium signaling; Endoplasmic reticulum stress; IRE1; Membrane contact sites; Mitochondria
  4. Cell Rep. 2019 Aug 20. pii: S2211-1247(19)30954-4. [Epub ahead of print]28(8): 1949-1960.e6
    Costa R, Peruzzo R, Bachmann M, Montà GD, Vicario M, Santinon G, Mattarei A, Moro E, Quintana-Cabrera R, Scorrano L, Zeviani M, Vallese F, Zoratti M, Paradisi C, Argenton F, Brini M, Calì T, Dupont S, Szabò I, Leanza L.
      Wnt signaling affects fundamental development pathways and, if aberrantly activated, promotes the development of cancers. Wnt signaling is modulated by different factors, but whether the mitochondrial energetic state affects Wnt signaling is unknown. Here, we show that sublethal concentrations of different compounds that decrease mitochondrial ATP production specifically downregulate Wnt/β-catenin signaling in vitro in colon cancer cells and in vivo in zebrafish reporter lines. Accordingly, fibroblasts from a GRACILE syndrome patient and a generated zebrafish model lead to reduced Wnt signaling. We identify a mitochondria-Wnt signaling axis whereby a decrease in mitochondrial ATP reduces calcium uptake into the endoplasmic reticulum (ER), leading to endoplasmic reticulum stress and to impaired Wnt signaling. In turn, the recovery of the ATP level or the inhibition of endoplasmic reticulum stress restores Wnt activity. These findings reveal a mechanism that links mitochondrial energetic metabolism to the control of the Wnt pathway that may be beneficial against several pathologies.
    Keywords:  ER stress; SERCA; canonical Wnt signaling; colon cancer; mitochondrial ATP; mitochondrial fitness; β-catenin
  5. J Cell Sci. 2019 Aug 21. pii: jcs.223891. [Epub ahead of print]
    Wagner A, Hofmeister O, Rolland SG, Maiser A, Aasumets K, Schmitt S, Schorpp K, Feuchtinger A, Hadian K, Schneider S, Zischka H, Leonhardt H, Conradt B, Gerhold JM, Wolf A.
      The Fe(II) and 2-oxoglutarate dependent oxygenase Alkb homolog 1 (Alkbh1) has been shown to act on a wide range of substrates, like DNA, tRNA or histones. Thereby different enzymatic activities have been identified including, amongst others demethylation of N 3-methylcytosine (m3C) in RNA- and single-stranded DNA-oligonucleotides, demethylation of N 1-methyladenosine (m1A) in tRNA or formation of 5-formyl cytosine (f5C) in tRNA. In accordance with the different substrates Alkbh1 has also been proposed to reside in distinct cellular compartments in human and mouse cells, including the nucleus, cytoplasm and mitochondria. Here we describe further evidence for a role of human Alkbh1 in regulation of mitochondrial protein biogenesis, including localisation of Alkbh1 into mitochondrial RNA granules with super-resolution 3D SIM microscopy. Electron microscopy and high-resolution respirometry analyses revealed an impact of Alkbh1 level on mitochondrial respiration, but not on mitochondrial structure. Downregulation of Alkbh1 impacts cell growth in Hela cells and delays development in C. elegans, where the mitochondrial role of Alkbh1 seems to be conserved. Alkbh1 knockdown, but not Alkbh7 knockdown, triggers mitochondrial unfolded protein response (UPRmt) in C. elegans.
    Keywords:  Fe(II) and 2-oxoglutarate dependent oxygenases; Jumonji-domain containing enzymes; Mitochondrial structure; Mitochondrial unfolded-protein response; RNA granules; RNA modifications