bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒05‒26
four papers selected by
Susan Logue
University of Manitoba

  1. Nat Cell Biol. 2019 May 20.
    Carreras-Sureda A, Jaña F, Urra H, Durand S, Mortenson DE, Sagredo A, Bustos G, Hazari Y, Ramos-Fernández E, Sassano ML, Pihán P, van Vliet AR, González-Quiroz M, Torres AK, Tapia-Rojas C, Kerkhofs M, Vicente R, Kaufman RJ, Inestrosa NC, Gonzalez-Billault C, Wiseman RL, Agostinis P, Bultynck G, Court FA, Kroemer G, Cárdenas JC, Hetz C.
      Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions. IRE1α determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1α at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1α conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1α in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics.
  2. Proc Natl Acad Sci U S A. 2019 May 23. pii: 201814480. [Epub ahead of print]
    Liu L, Cai J, Wang H, Liang X, Zhou Q, Ding C, Zhu Y, Fu T, Guo Q, Xu Z, Xiao L, Liu J, Yin Y, Fang L, Xue B, Wang Y, Meng ZX, He A, Li JL, Liu Y, Chen XW, Gan Z.
      The cytoplasmic coat protein complex-II (COPII) is evolutionarily conserved machinery that is essential for efficient trafficking of protein and lipid cargos. How the COPII machinery is regulated to meet the metabolic demand in response to alterations of the nutritional state remains largely unexplored, however. Here, we show that dynamic changes of COPII vesicle trafficking parallel the activation of transcription factor X-box binding protein 1 (XBP1s), a critical transcription factor in handling cellular endoplasmic reticulum (ER) stress in both live cells and mouse livers upon physiological fluctuations of nutrient availability. Using live-cell imaging approaches, we demonstrate that XBP1s is sufficient to promote COPII-dependent trafficking, mediating the nutrient stimulatory effects. Chromatin immunoprecipitation (ChIP) coupled with high-throughput DNA sequencing (ChIP-seq) and RNA-sequencing analyses reveal that nutritional signals induce dynamic XBP1s occupancy of promoters of COPII traffic-related genes, thereby driving the COPII-mediated trafficking process. Liver-specific disruption of the inositol-requiring enzyme 1α (IRE1α)-XBP1s signaling branch results in diminished COPII vesicle trafficking. Reactivation of XBP1s in mice lacking hepatic IRE1α restores COPII-mediated lipoprotein secretion and reverses the fatty liver and hypolipidemia phenotypes. Thus, our results demonstrate a previously unappreciated mechanism in the metabolic control of liver protein and lipid trafficking: The IRE1α-XBP1s axis functions as a nutrient-sensing regulatory nexus that integrates nutritional states and the COPII vesicle trafficking.
    Keywords:  COPII; XBP1s; liver steatosis; metabolic sensing; nutrient availability
  3. FEBS J. 2019 May 22.
    Wilkinson S.
      The endoplasmic reticulum (ER) network has central roles in metabolism and cellular organisation. The ER undergoes dynamic alterations in morphology, molecular composition and functional specification. Remodelling of the network under fluctuating conditions enables the continual performance of ER functions and minimises stress. Recent data have revealed that selective autophagy-mediated degradation of ER fragments, or ER-phagy, fundamentally contributes to this remodelling. This review provides a perspective on established views of selective autophagy, comparing these with emerging mechanisms of ER-phagy and related processes. The text discusses the impact of ER-phagy on the function of the ER and the cell, both in normal physiology and when dysregulated within disease settings. Finally, unanswered questions regarding the mechanisms and significance of ER-phagy are highlighted. This article is protected by copyright. All rights reserved.
    Keywords:   ERLAD ; ER-phagy; FAM134B; microautophagy; recovER-phagy
  4. Infect Immun. 2019 May 20. pii: IAI.00826-18. [Epub ahead of print]
    Mendez JM, Kolora LD, Lemon JS, Dupree SL, Keestra-Gounder AM.
      Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular pattern-recognition receptor (PRR) responsible for sensing bacterial peptidoglycan fragments. Stimulation of NOD1 leads to a robust innate immune response via activation of the major transcription factor NF-κB. In addition to peptidoglycan sensing, NOD1, and the closely related PRR NOD2, have been linked to inflammation by responding to the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR). Here we show, that differential ER stress induction renders cells more susceptible to a Salmonella Typhimurium infection in a NOD1-dependent manner measured by increased NF-kB activation and cytokine expression. In HeLa57A cells, stably transfected with a NF-κB::luciferase reporter, we show that cells undergoing ER stress induced by thapsigargin display a significant increase in NF-κB activation in response to NOD1 stimulation by C12-iE-DAP and the S Typhimurium effector protein SopE. Tunicamycin-induced ER stress had no effect on NOD1 stimulated NF-κB activation. We further show that the mouse intestinal epithelial cell line MODE-K and RAW264.7 macrophages are more responsive to Salmonella infection when treated with thapsigargin but not with tunicamycin. These profound differences between thapsigargin and tunicamycin treated cells on inflammation suggest that different components downstream of the UPR contribute to NOD1 activation. We found that the NOD1-induced inflammatory response is dependent on protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) activation in conjunction with stimulation of the inositol triphosphate receptor (IP3R). Together, these results suggest that differential UPR activation makes cells more responsive to bacterial infections in a NOD1-dependent manner.