SnapShot: The Unfolded Protein Response

The Scripps Research Institute, La Jolla, CA, USA
Cell (Impact Factor: 32.24). 02/2010; 140(4):590-590.e2. DOI: 10.1016/j.cell.2010.02.006
Source: PubMed
Download full-text


Available from: Rockland Luke Wiseman, Oct 13, 2015
37 Reads
  • Source
    • "In response to disturbed endoplasmic reticulum (ER) homeostasis, signaling pathways known as unfolded protein response (UPR) signaling are induced to restore the protein folding capacity of ER. These signaling pathways are transduced by three sensor proteins PERK, IRE1α, and ATF6α to restore protein folding in a translational-and transcriptional-dependent manner (Wiseman et al., 2010). In addition to this fundamental chaperon function, UPR is found to be associated with the pathogenesis of various diseases/disorders such as inflammation , obesity, diabetes, atherosclerosis and neurodegeneration (Cnop et al., 2012; Wang and Kaufman, 2012; Zhang, 2010; Zhang and Kaufman, 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon, 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses.
    Toxicology and Applied Pharmacology 08/2013; 272(3). DOI:10.1016/j.taap.2013.08.004 · 3.71 Impact Factor
  • Source
    • "Disruption of the COPII complex not only blocks protein trafficking but also activates the unfolded protein response (UPR). In metazoa, the UPR is mediated by three distinct membrane-bound stress sensors—IRE1a, ATF6, and PERK (Hetz and Glimcher, 2009; Wiseman et al., 2010). The UPR is a cellular response to cope with ER stress (Higashio and Kohno, 2002; Saito et al., 2011), such as that caused under pharmacological or pathological condition (Cinaroglu et al., 2011; Pyati et al., 2011; Thakur et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Sec13-Sec31 heterotetramer serves as the outer coat in the COPII complex, which mediates protein trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus. Although it has been studied in depth in yeast and cultured cells, the role of COPII in organogenesis in a multicellular organism has not. We report here that a zebrafish sec13(sq198) mutant, which exhibits a phenotype of hypoplastic digestive organs, has a mutation in the sec13 gene. The mutant gene encodes a carboxyl-terminus-truncated Sec13 that loses its affinity to Sec31a, which leads to disintegration of the ER structure in various differentiated cells in sec13(sq198), including chondrocytes, intestinal epithelial cells and hepatocytes. Disruption of the ER structure activates an unfolded protein response that eventually causes the cells to undergo cell-cycle arrest and cell apoptosis, which arrest the growth of developing digestive organs in the mutant. Our data provide the first direct genetic evidence that COPII function is essential for the organogenesis of the digestive system.
    Developmental Biology 05/2012; 367(2):197-207. DOI:10.1016/j.ydbio.2012.05.004 · 3.55 Impact Factor
  • Source
    • "Significantly, blockade of the ER-to-Golgi transport by the ectopic expression of STX5, Arf1-Q71L, and Sar1-T39N evoked an induction of CHOP in HEK293 cells (Figure 4A). Three different classes of ER stress signal transducers, IRE1, PERK, and ATF6, have been identified to mediate the UPR (Wiseman et al., 2010). Depletion of each transducer by treatment with specific siRNAs revealed that the IRE1-mediated signaling arm, but not those of PERK and ATF6, is involved in the ER stress-induced exocytosis of coreglycosylated CFTR (Figure 4B). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The most prevalent disease-causing mutation of CFTR is the deletion of Phe508 (ΔF508), which leads to defects in conventional Golgi-mediated exocytosis and cell surface expression. We report that ΔF508-CFTR surface expression can be rescued in vitro and in vivo by directing it to an unconventional GRASP-dependent secretion pathway. An integrated molecular and physiological analysis indicates that mechanisms associated with ER stress induce cell surface trafficking of the ER core-glycosylated wild-type and ΔF508-CFTR via the GRASP-dependent pathway. Phosphorylation of a specific site of GRASP and the PDZ-based interaction between GRASP and CFTR are critical for this unconventional surface trafficking. Remarkably, transgenic expression of GRASP in ΔF508-CFTR mice restores CFTR function and rescues mouse survival without apparent toxicity. These findings provide insight into how unconventional protein secretion is activated, and offer a potential therapeutic strategy for the treatment of cystic fibrosis and perhaps diseases stemming from other misfolded proteins.
    Cell 09/2011; 146(5):746-60. DOI:10.1016/j.cell.2011.07.021 · 32.24 Impact Factor
Show more