bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒09‒22
eight papers selected by
Susan Logue
University of Manitoba


  1. Cell Death Discov. 2019 ;5 134
    Prieto K, Cao Y, Mohamed E, Trillo-Tinoco J, Sierra RA, Urueña C, Sandoval TA, Fiorentino S, Rodriguez PC, Barreto A.
      Polyphenols elicit antitumor activities, in part, through the induction of anti- or pro-oxidant effects in cancer cells which promote priming of protective anti-tumor immunity. We recently characterized a polyphenol-rich extract from Caesalpinia spinosa (P2Et) that stimulates in vivo antitumor responses against breast and melanoma tumor models via the promotion of immunogenic cancer cell death (ICD). However, the primary mediators whereby P2Et promotes ICD remained unknown. Here, we sought to elucidate the role that severe endoplasmic reticulum (ER) stress plays in mediating P2Et-induced apoptosis and ICD in murine melanoma cells. Our findings demonstrate a substantial selective induction of specific ER-stress mediators in B16-F10 melanoma cells treated with P2Et. While knockout of the ER stress-associated PKR-like ER kinase (PERK) prevented induction of apoptosis and expression of ICD markers in P2Et-treated cells, deletion of X-box binding protein 1 (Xbp1) did not. P2Et-driven activation of PERK in melanoma cells was found to promote ER-calcium release, disrupt mitochondrial membrane potential, and trigger upregulation of ICD drivers, surface calreticulin expression, and extracellular release of ATP and HMGB1. Notably, calcium release inhibition, but not targeting of PERK-driven integrated stress responses, prevented P2Et-induced apoptosis. Collectively, these results underline the central role of PERK-directed calcium release in mediating the antitumor and immunogenic actions of P2Et in melanoma cells.
    Keywords:  Cancer; Cell death
    DOI:  https://doi.org/10.1038/s41420-019-0214-2
  2. J Cell Biol. 2019 Sep 19. pii: jcb.201906047. [Epub ahead of print]
    Sun Z, Brodsky JL.
      Protein folding is inherently error prone, especially in the endoplasmic reticulum (ER). Even with an elaborate network of molecular chaperones and protein folding facilitators, misfolding can occur quite frequently. To maintain protein homeostasis, eukaryotes have evolved a series of protein quality-control checkpoints. When secretory pathway quality-control pathways fail, stress response pathways, such as the unfolded protein response (UPR), are induced. In addition, the ER, which is the initial hub of protein biogenesis in the secretory pathway, triages misfolded proteins by delivering substrates to the proteasome or to the lysosome/vacuole through ER-associated degradation (ERAD) or ER-phagy. Some misfolded proteins escape the ER and are instead selected for Golgi quality control. These substrates are targeted for degradation after retrieval to the ER or delivery to the lysosome/vacuole. Here, we discuss how these guardian pathways function, how their activities intersect upon induction of the UPR, and how decisions are made to dispose of misfolded proteins in the secretory pathway.
    DOI:  https://doi.org/10.1083/jcb.201906047
  3. Cell Death Dis. 2019 Sep 18. 10(10): 690
    Peñaranda-Fajardo NM, Meijer C, Liang Y, Dijkstra BM, Aguirre-Gamboa R, den Dunnen WFA, Kruyt FAE.
      Patients with aggressive brain tumors, named glioblastoma multiforme (GBM), have a poor prognoses. Here we explored if the ER stress/unfolded protein response (UPR) is involved in the pathophysiology of GBM and may provide novel therapeutic targets. Immunohistochemical analyses of a tissue microarray containing primary GBM specimens showed strong variability in expression of the UPR markers GRP78/BiP, XBP1, and ATF4. Interestingly, high ATF4 expression was associated with poor overall survival suggesting involvement of PERK signaling in GBM progression. In vitro experiments using patient-derived neurospheres, enriched for GBM stem cells (GSCs), showed high sensitivity for the ER stressor thapsigargin (Tg) mainly via PERK signaling. In contrast, neurospheres-derived differentiated GBM cells were less sensitive likely due to lower UPR activity as indicated by comparative transcriptional profiling. Tg and Tunicamycin strongly reduced neurosphere forming ability of GSCs that was linked with potent PERK-dependent downregulation of SOX2 protein. Interestingly, SOX2 downregulation occurred directly via PERK, not requiring downstream activation of the PERK-UPR pathway. Moreover, PERK inactivation resulted in aberrant serum-induced differentiation of GBM neurospheres accompanied by persistent SOX2 expression, delayed upregulation of GFAP and reduced cell adherence. In conclusion, we provide evidence that PERK signaling contributes to the prognoses of primary GBM patients and identified PERK as a novel regulator of SOX2 expression and GSC differentiation. The role of PERK appeared to be pleiotropic involving UPR-dependent, as well as novel identified noncanonical mechanisms regulating SOX2. ER stress and PERK modulation appear to provide promising therapeutic targets for therapy in GBM.
    DOI:  https://doi.org/10.1038/s41419-019-1934-1
  4. EMBO J. 2019 Sep 18. e102177
    Perera LA, Rato C, Yan Y, Neidhardt L, McLaughlin SH, Read RJ, Preissler S, Ron D.
      AMPylation is an inactivating modification that alters the activity of the major endoplasmic reticulum (ER) chaperone BiP to match the burden of unfolded proteins. A single ER-localised Fic protein, FICD (HYPE), catalyses both AMPylation and deAMPylation of BiP. However, the basis for the switch in FICD's activity is unknown. We report on the transition of FICD from a dimeric enzyme, that deAMPylates BiP, to a monomer with potent AMPylation activity. Mutations in the dimer interface, or of residues along an inhibitory pathway linking the dimer interface to the enzyme's active site, favour BiP AMPylation in vitro and in cells. Mechanistically, monomerisation relieves a repressive effect allosterically propagated from the dimer interface to the inhibitory Glu234, thereby permitting AMPylation-competent binding of MgATP. Moreover, a reciprocal signal, propagated from the nucleotide-binding site, provides a mechanism for coupling the oligomeric state and enzymatic activity of FICD to the energy status of the ER.
    Keywords:   FICD ; AMPylation; BiP; deAMPylation; endoplasmic reticulum
    DOI:  https://doi.org/10.15252/embj.2019102177
  5. Autophagy. 2019 Sep 19. 1-2
    Mollereau B, Walter L.
      Beta-propeller protein-associated neurodegeneration (BPAN) is caused by mutations in the autophagy gene WDR45/WIPI4. In human, BPAN is associated with static encephalopathy in childhood and neurodegeneration in adulthood (SENDA). It has been proposed that WDR45 mutations cause neurodegeneration due to defective autophagy. Whether these mutations cause a global attenuation or a defect in a subset of autophagy functions is unknown. Based on a recent study showing that wdr45 knockout mice exhibit defective autophagy associated with an increased ER stress, we propose that ER-mediated autophagy, a selective activation of autophagy, is defective in mouse and cellular models of BPAN. We discuss the implication of these findings on the pathophysiological relevance of the relationship between ER stress and autophagy in BPAN as well as other neurodegenerative diseases exhibiting ER stress and defective autophagy.
    Keywords:  Autophagy; BPAN; ER stress; beta propeller associated neurodegeneration; neurodegeneration
    DOI:  https://doi.org/10.1080/15548627.2019.1668229
  6. Neuron. 2019 Aug 26. pii: S0896-6273(19)30691-9. [Epub ahead of print]
    Pathak SS, Liu D, Li T, de Zavalia N, Zhu L, Li J, Karthikeyan R, Alain T, Liu AC, Storch KF, Kaufman RJ, Jin VX, Amir S, Sonenberg N, Cao R.
      The integrated stress response (ISR) is activated in response to diverse stress stimuli to maintain homeostasis in neurons. Central to this process is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Here, we report a critical role for ISR in regulating the mammalian circadian clock. The eIF2α kinase GCN2 rhythmically phosphorylates eIF2α in the suprachiasmatic circadian clock. Increased eIF2α phosphorylation shortens the circadian period in both fibroblasts and mice, whereas reduced eIF2α phosphorylation lengthens the circadian period and impairs circadian rhythmicity in animals. Mechanistically, phosphorylation of eIF2α promotes mRNA translation of Atf4. ATF4 binding motifs are identified in multiple clock genes, including Per2, Per3, Cry1, Cry2, and Clock. ATF4 binds to the TTGCAGCA motif in the Per2 promoter and activates its transcription. Together, these results demonstrate a significant role for ISR in circadian physiology and provide a potential link between dysregulated ISR and circadian dysfunction in brain diseases.
    Keywords:  ATF4; GCN2; Per2; SCN; circadian clock; eIF2; mouse
    DOI:  https://doi.org/10.1016/j.neuron.2019.08.007
  7. Exp Mol Med. 2019 Sep 20. 51(9): 107
    Bang IH, Kwon OK, Hao L, Park D, Chung MJ, Oh BC, Lee S, Bae EJ, Park BH.
      The active spliced form of X-box-binding protein 1 (XBP1s) is a key modulator of ER stress, but the functional role of its post-translational modification remains unclear. Here, we demonstrate that XBP1s is a deacetylation target of Sirt6 and that its deacetylation protects against ER stress-induced hepatic steatosis. Specifically, the abundance of acetylated XBP1s and concordant hepatic steatosis were increased in hepatocyte-specific Sirt6 knockout and obese mice but were decreased by genetic overexpression and pharmacological activation of Sirt6. Mechanistically, we identified that Sirt6 deacetylated a transactivation domain of XBP1s at Lys257 and Lys297 and promoted XBP1s protein degradation through the ubiquitin-proteasome system. Overexpression of XBP1s, but not its deacetylation mutant 2KR (K257/297R), in mice increased lipid accumulation in the liver. Importantly, in liver tissues obtained from patients with nonalcoholic fatty liver disease (NAFLD), the extent of XBP1s acetylation correlated positively with the NAFLD activity score but negatively with the Sirt6 level. Collectively, we present direct evidence supporting the importance of XBP1 acetylation in ER stress-induced hepatic steatosis.
    DOI:  https://doi.org/10.1038/s12276-019-0309-0
  8. Cells. 2019 Sep 15. pii: E1088. [Epub ahead of print]8(9):
    Namgaladze D, Khodzhaeva V, Brüne B.
      In cells the interorganelle communication comprises vesicular and non-vesicular mechanisms. Non-vesicular material transfer predominantly takes place at regions of close organelle apposition termed membrane contact sites and is facilitated by a growing number of specialized proteins. Contacts of the endoplasmic reticulum (ER) and mitochondria are now recognized to be essential for diverse biological processes such as calcium homeostasis, phospholipid biosynthesis, apoptosis, and autophagy. In addition to these universal roles, ER-mitochondria communication serves also cell type-specific functions. In this review, we summarize the current knowledge on ER-mitochondria contacts in cells of the innate immune system, especially in macrophages. We discuss ER- mitochondria communication in the context of macrophage fatty acid metabolism linked to inflammatory and ER stress responses, its roles in apoptotic cell engulfment, activation of the inflammasome, and antiviral defense.
    Keywords:  endoplasmic reticulum; inflammation; lipid metabolism; macrophages; mitochondria
    DOI:  https://doi.org/10.3390/cells8091088